rs2246841

chr9-104840385-C-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.948G>A(p.Gly316=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,614,046 control chromosomes in the GnomAD database, including 11,625 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1871 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9754 hom.)
• Consequence: ABCA1 NM_005502.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.58

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=-0.44).
• BP6: Variant 9-104840385-C-T is Benign according to our data. Variant chr9-104840385-C-T is described in ClinVar as [Benign]. Clinvar id is 364450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-104840385-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA1	NM_005502.4	c.948G>A	p.Gly316=	synonymous_variant	9/50	ENST00000374736.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA1	ENST00000374736.8	c.948G>A	p.Gly316=	synonymous_variant	9/50	1	NM_005502.4	P1
ABCA1	ENST00000678995.1	c.948G>A	p.Gly316=	synonymous_variant	9/50

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22010 AN: 152080 Hom.: 1873 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.0988

Gnomad EAS AF: 0.0276

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.0723

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.148

GnomAD3 exomes AF: 0.122 AC: 30764 AN: 251424 Hom.: 2290 AF XY: 0.121 AC XY: 16503 AN XY: 135888

Gnomad AFR exome AF: 0.231

Gnomad AMR exome AF: 0.178

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.0197

Gnomad SAS exome AF: 0.156

Gnomad FIN exome AF: 0.0738

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.110 AC: 161130 AN: 1461848 Hom.: 9754 Cov.: 33 AF XY: 0.111 AC XY: 81027 AN XY: 727222

Gnomad4 AFR exome AF: 0.231

Gnomad4 AMR exome AF: 0.179

Gnomad4 ASJ exome AF: 0.0958

Gnomad4 EAS exome AF: 0.0425

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.0784

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.117

GnomAD4 genome AF: 0.145 AC: 22034 AN: 152198 Hom.: 1871 Cov.: 32 AF XY: 0.144 AC XY: 10703 AN XY: 74432

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.0988

Gnomad4 EAS AF: 0.0278

Gnomad4 SAS AF: 0.153

Gnomad4 FIN AF: 0.0723

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.147

Alfa AF: 0.113 Hom.: 1976

Bravo AF: 0.154

Asia WGS AF: 0.100 AC: 347 AN: 3478

EpiCase AF: 0.117

EpiControl AF: 0.112

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 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

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	1.8
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: rs2246841; hg19: chr9-107602666; COSMIC: COSV66067636;