NM_005502.4:c.2320A>C

Variant names:

• chr9-104826965-T-G
• rs35819696
• NM_005502.4:c.2320A>C

Variant summary

Our verdict is Benign. The variant received -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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• 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
• Publications: 25 publications found

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]

ABCA1 Gene-Disease associations (from GenCC):

• hypoalphalipoproteinemia, primary, 1

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Tangier disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• apolipoprotein A-I deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 364431.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005502.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	NM_005502.4	MANE Select	c.2320A>C	p.Thr774Pro	missense	Exon 16 of 50	NP_005493.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	ENST00000374736.8	TSL:1 MANE Select	c.2320A>C	p.Thr774Pro	missense	Exon 16 of 50	ENSP00000363868.3
	ABCA1	ENST00000678995.1		c.2320A>C	p.Thr774Pro	missense	Exon 16 of 50	ENSP00000504612.1
	ABCA1	ENST00000494467.1	TSL:3	n.493A>C		non_coding_transcript_exon	Exon 3 of 4

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

GnomAD2 exomes AF: 0.00210 AC: 526 AN: 250674 AF XY: 0.00210

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 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

African (AFR) AF: 0.000717 AC: 24 AN: 33478

American (AMR) AF: 0.00338 AC: 151 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86244

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53336

Middle Eastern (MID) AF: 0.00159 AC: 9 AN: 5666

European-Non Finnish (NFE) AF: 0.00401 AC: 4464 AN: 1111992

Other (OTH) AF: 0.00321 AC: 194 AN: 60374

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

African (AFR) AF: 0.000842 AC: 35 AN: 41560

American (AMR) AF: 0.00739 AC: 113 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00406 AC: 276 AN: 68016

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00300 Hom.: 4

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypoalphalipoproteinemia, primary, 1 (1)
-	-	1	not specified (1)
-	1	-	Tangier disease (1)
-	1	-	Tangier disease;C5231558:Hypoalphalipoproteinemia, primary, 1 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.78
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
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs35819696; hg19: chr9-107589246;