rs2274873

chr9-104840397-G-Achr9-104840397-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005502.4(ABCA1):c.936C>T(p.Pro312=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0969 in 1,614,018 control chromosomes in the GnomAD database, including 7,922 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (702 hom., cov: 32)
  • Exomes 𝑓: 0.097 (7220 hom.)
• Consequence: ABCA1 NM_005502.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.18

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 9-104840397-G-A is Benign according to our data. Variant chr9-104840397-G-A is described in ClinVar as [Benign]. Clinvar id is 364451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-104840397-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.18 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0969 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA1	NM_005502.4	c.936C>T	p.Pro312=	synonymous_variant	9/50	ENST00000374736.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA1	ENST00000374736.8	c.936C>T	p.Pro312=	synonymous_variant	9/50	1	NM_005502.4	P1
ABCA1	ENST00000678995.1	c.936C>T	p.Pro312=	synonymous_variant	9/50

Frequencies

GnomAD3 genomes AF: 0.0921 AC: 14010 AN: 152044 Hom.: 703 Cov.: 32

Gnomad AFR AF: 0.0972

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.0578

Gnomad ASJ AF: 0.0822

Gnomad EAS AF: 0.0702

Gnomad SAS AF: 0.0838

Gnomad FIN AF: 0.0886

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0988

Gnomad OTH AF: 0.0836

GnomAD3 exomes AF: 0.0848 AC: 21313 AN: 251422 Hom.: 1017 AF XY: 0.0865 AC XY: 11760 AN XY: 135890

Gnomad AFR exome AF: 0.0966

Gnomad AMR exome AF: 0.0379

Gnomad ASJ exome AF: 0.0864

Gnomad EAS exome AF: 0.0671

Gnomad SAS exome AF: 0.0895

Gnomad FIN exome AF: 0.0819

Gnomad NFE exome AF: 0.0993

Gnomad OTH exome AF: 0.0844

GnomAD4 exome AF: 0.0974 AC: 142332 AN: 1461856 Hom.: 7220 Cov.: 34 AF XY: 0.0974 AC XY: 70811 AN XY: 727224

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.0393

Gnomad4 ASJ exome AF: 0.0858

Gnomad4 EAS exome AF: 0.0917

Gnomad4 SAS exome AF: 0.0857

Gnomad4 FIN exome AF: 0.0832

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.0964

GnomAD4 genome AF: 0.0922 AC: 14023 AN: 152162 Hom.: 702 Cov.: 32 AF XY: 0.0900 AC XY: 6697 AN XY: 74376

Gnomad4 AFR AF: 0.0973

Gnomad4 AMR AF: 0.0578

Gnomad4 ASJ AF: 0.0822

Gnomad4 EAS AF: 0.0698

Gnomad4 SAS AF: 0.0830

Gnomad4 FIN AF: 0.0886

Gnomad4 NFE AF: 0.0988

Gnomad4 OTH AF: 0.0851

Alfa AF: 0.0964 Hom.: 1707

Bravo AF: 0.0893

Asia WGS AF: 0.105 AC: 364 AN: 3478

EpiCase AF: 0.103

EpiControl AF: 0.0997

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

ABCA1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2018

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. -

Tangier disease 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. -

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
BayesDel_noAF	Benign	-0.38
Cadd	Benign	0.35
Dann	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2274873; hg19: chr9-107602678; COSMIC: COSV66064796;