9-104826974-C-T

Position:

• chr9-104826974-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005502.4(ABCA1):​c.2311G>A​(p.Val771Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0394 in 1,613,990 control chromosomes in the GnomAD database, including 1,908 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V771L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.058 (346 hom., cov: 33)
  • Exomes 𝑓: 0.037 (1562 hom.)
• Consequence: ABCA1 NM_005502.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.80

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017911494).
• BP6: Variant 9-104826974-C-T is Benign according to our data. Variant chr9-104826974-C-T is described in ClinVar as [Benign]. Clinvar id is 364433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-104826974-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA1	NM_005502.4	c.2311G>A	p.Val771Met	missense_variant	16/50	ENST00000374736.8	NP_005493.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA1	ENST00000374736.8	c.2311G>A	p.Val771Met	missense_variant	16/50	1	NM_005502.4	ENSP00000363868.3
ABCA1	ENST00000678995.1	c.2311G>A	p.Val771Met	missense_variant	16/50			ENSP00000504612.1
ABCA1	ENST00000494467.1	n.484G>A		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes AF: 0.0580 AC: 8824 AN: 152138 Hom.: 347 Cov.: 33

Gnomad AFR AF: 0.0946

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0533

Gnomad EAS AF: 0.0269

Gnomad SAS AF: 0.0634

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0315

Gnomad OTH AF: 0.0689

GnomAD3 exomes AF: 0.0541 AC: 13584 AN: 250888 Hom.: 633 AF XY: 0.0518 AC XY: 7030 AN XY: 135656

Gnomad AFR exome AF: 0.0949

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.0500

Gnomad EAS exome AF: 0.0196

Gnomad SAS exome AF: 0.0641

Gnomad FIN exome AF: 0.0141

Gnomad NFE exome AF: 0.0334

Gnomad OTH exome AF: 0.0580

GnomAD4 exome AF: 0.0374 AC: 54721 AN: 1461734 Hom.: 1562 Cov.: 32 AF XY: 0.0379 AC XY: 27543 AN XY: 727174

Gnomad4 AFR exome AF: 0.0892

Gnomad4 AMR exome AF: 0.136

Gnomad4 ASJ exome AF: 0.0492

Gnomad4 EAS exome AF: 0.0426

Gnomad4 SAS exome AF: 0.0640

Gnomad4 FIN exome AF: 0.0160

Gnomad4 NFE exome AF: 0.0297

Gnomad4 OTH exome AF: 0.0462

GnomAD4 genome AF: 0.0580 AC: 8835 AN: 152256 Hom.: 346 Cov.: 33 AF XY: 0.0585 AC XY: 4360 AN XY: 74476

Gnomad4 AFR AF: 0.0945

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.0533

Gnomad4 EAS AF: 0.0272

Gnomad4 SAS AF: 0.0632

Gnomad4 FIN AF: 0.0136

Gnomad4 NFE AF: 0.0315

Gnomad4 OTH AF: 0.0691

Alfa AF: 0.0357 Hom.: 214

Bravo AF: 0.0662

TwinsUK AF: 0.0267 AC: 99

ALSPAC AF: 0.0278 AC: 107

ESP6500AA AF: 0.0915 AC: 403

ESP6500EA AF: 0.0363 AC: 312

ExAC AF: 0.0512 AC: 6210

EpiCase AF: 0.0365

EpiControl AF: 0.0344

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	This variant is associated with the following publications: (PMID: 15520867, 24503134) -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2019

This alteration is classified as 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

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Tangier disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Benign	0.097
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.47	N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.65	N
REVEL	Benign	0.18
Sift	Benign	0.78	T
Sift4G	Benign	1.0	T
Polyphen		0.074	B
Vest4		0.086
MPC		0.27
ClinPred		0.0074	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.33

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: rs2066718; hg19: chr9-107589255;