rs35819696

Positions:

• chr9-104826965-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005502.4(ABCA1):​c.2320A>C​(p.Thr774Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,613,942 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T774S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (8 hom.)
• Consequence: ABCA1 NM_005502.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 0.780

Genes affected

ABCA1 (HGNC:29): (ATP binding cassette subfamily A member 1) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. With cholesterol as its substrate, this protein functions as a cholesteral efflux pump in the cellular lipid removal pathway. Mutations in both alleles of this gene cause Tangier disease and familial high-density lipoprotein (HDL) deficiency. [provided by RefSeq, Sep 2019]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012717336).
• BP6: Variant 9-104826965-T-G is Benign according to our data. Variant chr9-104826965-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 364431.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=3}. Variant chr9-104826965-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00286 (436/152294) while in subpopulation AMR AF= 0.00739 (113/15300). AF 95% confidence interval is 0.00628. There are 1 homozygotes in gnomad4. There are 183 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA1	NM_005502.4	c.2320A>C	p.Thr774Pro	missense_variant	16/50	ENST00000374736.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA1	ENST00000374736.8	c.2320A>C	p.Thr774Pro	missense_variant	16/50	1	NM_005502.4	P1
ABCA1	ENST00000678995.1	c.2320A>C	p.Thr774Pro	missense_variant	16/50
ABCA1	ENST00000494467.1	n.493A>C		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 436 AN: 152176 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00406

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00210 AC: 526 AN: 250674 Hom.: 1 AF XY: 0.00210 AC XY: 284 AN XY: 135544

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00318

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00334 AC: 4887 AN: 1461648 Hom.: 8 Cov.: 32 AF XY: 0.00335 AC XY: 2435 AN XY: 727126

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00338

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00401

Gnomad4 OTH exome AF: 0.00321

GnomAD4 genome AF: 0.00286 AC: 436 AN: 152294 Hom.: 1 Cov.: 33 AF XY: 0.00246 AC XY: 183 AN XY: 74474

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00739

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00406

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00290 Hom.: 1

Bravo AF: 0.00309

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00166 AC: 201

EpiCase AF: 0.00316

EpiControl AF: 0.00350

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2021	This variant is associated with the following publications: (PMID: 11238261, 24497850, 15297675) -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 05, 2016	Variant summary: The ABCA1 c.2320A>C (p.Thr774Pro) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant. This variant was found in 201/121258 control chromosomes (1 homozygote) at a frequency of 0.0016576, which is approximately 133 times the estimated maximal expected allele frequency of a pathogenic ABCA1 variant (0.0000125), suggesting this variant is likely a benign polymorphism. This variant has been shown to not be associated with lipid levels or CAD phenotype (Clee_2001). Further evidence toward benign classification is that one internal sample carries this variant and LDLR c.1291G>A (pathogenic). In addition, the cholesterol efflux was within the normal range in cells from two individuals who had this variant (Cohen_2004). Taken together, this variant is classified as benign. -

Tangier disease;C5231558:Hypoalphalipoproteinemia, primary, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jul 02, 2021

- -

Tangier disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 25, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hypoalphalipoproteinemia, primary, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.39	N
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.68	N
REVEL	Uncertain	0.38
Sift	Benign	0.24	T
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.49
MVP		0.93
MPC		0.27
ClinPred		0.0026	T
GERP RS		1.5
Varity_R		0.37
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35819696; hg19: chr9-107589246;