rs2246841

Variant names:

• chr9-104840385-C-T
• rs2246841
• NM_005502.4:c.948G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005502.4(ABCA1):​c.948G>A​(p.Gly316Gly) 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:6
• Conservation: PhyloP100: -1.58
• Publications: 21 publications found

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 Gene-Disease associations (from GenCC):

• hypoalphalipoproteinemia, primary, 1

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Tangier disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• apolipoprotein A-I deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 364450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005502.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	NM_005502.4	MANE Select	c.948G>A	p.Gly316Gly	synonymous	Exon 9 of 50	NP_005493.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	ENST00000374736.8	TSL:1 MANE Select	c.948G>A	p.Gly316Gly	synonymous	Exon 9 of 50	ENSP00000363868.3	O95477
	ABCA1	ENST00000678995.1		c.948G>A	p.Gly316Gly	synonymous	Exon 9 of 50	ENSP00000504612.1	A0A7I2V5U0

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

GnomAD2 exomes AF: 0.122 AC: 30764 AN: 251424 AF XY: 0.121

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 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

African (AFR) AF: 0.231 AC: 7719 AN: 33478

American (AMR) AF: 0.179 AC: 8019 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0958 AC: 2504 AN: 26136

East Asian (EAS) AF: 0.0425 AC: 1689 AN: 39700

South Asian (SAS) AF: 0.156 AC: 13414 AN: 86254

European-Finnish (FIN) AF: 0.0784 AC: 4188 AN: 53416

Middle Eastern (MID) AF: 0.174 AC: 1003 AN: 5768

European-Non Finnish (NFE) AF: 0.104 AC: 115534 AN: 1111980

Other (OTH) AF: 0.117 AC: 7060 AN: 60396

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

African (AFR) AF: 0.232 AC: 9616 AN: 41504

American (AMR) AF: 0.174 AC: 2660 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0988 AC: 343 AN: 3470

East Asian (EAS) AF: 0.0278 AC: 144 AN: 5174

South Asian (SAS) AF: 0.153 AC: 736 AN: 4818

European-Finnish (FIN) AF: 0.0723 AC: 768 AN: 10620

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7243 AN: 68010

Other (OTH) AF: 0.147 AC: 311 AN: 2112

Alfa AF: 0.119 Hom.: 4842

Bravo AF: 0.154

Asia WGS AF: 0.100 AC: 347 AN: 3478

EpiCase AF: 0.117

EpiControl AF: 0.112

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypoalphalipoproteinemia, primary, 1 (1)
-	-	1	Tangier disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	1.8
DANN	Benign	0.63
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2246841; hg19: chr9-107602666; COSMIC: COSV66067636;