rs35871586

Variant names:

• chr9-104819668-A-C
• rs35871586
• NM_005502.4:c.3159T>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005502.4(ABCA1):​c.3159T>G​(p.Val1053Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00999 in 1,614,208 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (3 hom., cov: 32)
  • Exomes 𝑓: 0.010 (98 hom.)
• Consequence: ABCA1 NM_005502.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.148

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 9-104819668-A-C is Benign according to our data. Variant chr9-104819668-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 364421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-104819668-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.148 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00735 (1119/152314) while in subpopulation NFE AF= 0.0118 (801/68022). AF 95% confidence interval is 0.0111. There are 3 homozygotes in gnomad4. There are 505 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA1	NM_005502.4	c.3159T>G	p.Val1053Val	synonymous_variant	Exon 22 of 50	ENST00000374736.8	NP_005493.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA1	ENST00000374736.8	c.3159T>G	p.Val1053Val	synonymous_variant	Exon 22 of 50	1	NM_005502.4	ENSP00000363868.3
ABCA1	ENST00000678995.1	c.3159T>G	p.Val1053Val	synonymous_variant	Exon 22 of 50			ENSP00000504612.1

Frequencies

GnomAD3 genomes AF: 0.00735 AC: 1119 AN: 152196 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00750 AC: 1887 AN: 251452 Hom.: 11 AF XY: 0.00746 AC XY: 1014 AN XY: 135900

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00421

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.00961

GnomAD4 exome AF: 0.0103 AC: 15012 AN: 1461894 Hom.: 98 Cov.: 33 AF XY: 0.0100 AC XY: 7273 AN XY: 727248

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.00434

Gnomad4 ASJ exome AF: 0.00168

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00428

Gnomad4 FIN exome AF: 0.0116

Gnomad4 NFE exome AF: 0.0118

Gnomad4 OTH exome AF: 0.00922

GnomAD4 genome AF: 0.00735 AC: 1119 AN: 152314 Hom.: 3 Cov.: 32 AF XY: 0.00678 AC XY: 505 AN XY: 74484

Gnomad4 AFR AF: 0.00207

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.0105

Gnomad4 NFE AF: 0.0118

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00872 Hom.: 1

Bravo AF: 0.00648

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.0108

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCA1: BP4, BP7, BS1, BS2 -

May 30, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The ABCA1 c.3159T>G (p.Val1053Val) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 918/121410 control chromosomes (including 6 homozygotes) at a frequency of 0.0075612, which is approximately 605 times the estimated maximal expected allele frequency of a pathogenic ABCA1 variant (0.0000125), suggesting this variant is a benign polymorphism. One internal sample carrying this variant also carries another deleterious variant PCSK9 p.Tyr142X further supporting for benign outcome. Taken together, this variant is classified as Benign. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 10, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Sep 10, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.56
CADD	Benign	6.6
DANN	Benign	0.74

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: rs35871586; hg19: chr9-107581949;