9-104861748-C-T

Position:

• chr9-104861748-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005502.4(ABCA1):​c.474G>A​(p.Leu158Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,612,688 control chromosomes in the GnomAD database, including 66,663 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8536 hom., cov: 30)
  • Exomes 𝑓: 0.27 (58127 hom.)
• Consequence: ABCA1 NM_005502.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.352

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=-0.48).
• BP6: Variant 9-104861748-C-T is Benign according to our data. Variant chr9-104861748-C-T is described in ClinVar as [Benign]. Clinvar id is 364460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-104861748-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.352 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA1	NM_005502.4	c.474G>A	p.Leu158Leu	synonymous_variant	6/50	ENST00000374736.8	NP_005493.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA1	ENST00000374736.8	c.474G>A	p.Leu158Leu	synonymous_variant	6/50	1	NM_005502.4	ENSP00000363868.3
ABCA1	ENST00000678995.1	c.474G>A	p.Leu158Leu	synonymous_variant	6/50			ENSP00000504612.1
ABCA1	ENST00000423487.6	c.474G>A	p.Leu158Leu	synonymous_variant	6/8	2		ENSP00000416623.2
ABCA1	ENST00000374733.1	c.294G>A	p.Leu98Leu	synonymous_variant	5/5	2		ENSP00000363865.1

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49088 AN: 151292 Hom.: 8512 Cov.: 30

Gnomad AFR AF: 0.444

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.326

GnomAD3 exomes AF: 0.300 AC: 75312 AN: 251444 Hom.: 11923 AF XY: 0.300 AC XY: 40702 AN XY: 135892

Gnomad AFR exome AF: 0.445

Gnomad AMR exome AF: 0.306

Gnomad ASJ exome AF: 0.266

Gnomad EAS exome AF: 0.406

Gnomad SAS exome AF: 0.371

Gnomad FIN exome AF: 0.214

Gnomad NFE exome AF: 0.259

Gnomad OTH exome AF: 0.300

GnomAD4 exome AF: 0.275 AC: 401833 AN: 1461278 Hom.: 58127 Cov.: 33 AF XY: 0.278 AC XY: 202344 AN XY: 726970

Gnomad4 AFR exome AF: 0.447

Gnomad4 AMR exome AF: 0.309

Gnomad4 ASJ exome AF: 0.267

Gnomad4 EAS exome AF: 0.463

Gnomad4 SAS exome AF: 0.372

Gnomad4 FIN exome AF: 0.214

Gnomad4 NFE exome AF: 0.256

Gnomad4 OTH exome AF: 0.296

GnomAD4 genome AF: 0.325 AC: 49165 AN: 151410 Hom.: 8536 Cov.: 30 AF XY: 0.326 AC XY: 24114 AN XY: 73910

Gnomad4 AFR AF: 0.444

Gnomad4 AMR AF: 0.324

Gnomad4 ASJ AF: 0.264

Gnomad4 EAS AF: 0.407

Gnomad4 SAS AF: 0.381

Gnomad4 FIN AF: 0.219

Gnomad4 NFE AF: 0.259

Gnomad4 OTH AF: 0.330

Alfa AF: 0.267 Hom.: 9354

Bravo AF: 0.335

Asia WGS AF: 0.383 AC: 1329 AN: 3478

EpiCase AF: 0.276

EpiControl AF: 0.269

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	GeneDx	Aug 30, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.48
CADD	Benign	6.9
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2230805; hg19: chr9-107624029; COSMIC: COSV66057549;