NM_005502.4:c.303-39C>A

Variant names:

• chr9-104883196-G-T
• rs12003906
• NM_005502.4:c.303-39C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005502.4(ABCA1):​c.303-39C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,530,888 control chromosomes in the GnomAD database, including 1,848 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (923 hom., cov: 33)
  • Exomes 𝑓: 0.011 (925 hom.)
• Consequence: ABCA1 NM_005502.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.27
• Publications: 12 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• apolipoprotein A-I deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 9-104883196-G-T is Benign according to our data. Variant chr9-104883196-G-T is described in ClinVar as [Benign]. Clinvar id is 1248989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA1	NM_005502.4	c.303-39C>A		intron_variant	Intron 4 of 49	ENST00000374736.8	NP_005493.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA1	ENST00000374736.8	c.303-39C>A		intron_variant	Intron 4 of 49	1	NM_005502.4	ENSP00000363868.3
ABCA1	ENST00000678995.1	c.303-39C>A		intron_variant	Intron 4 of 49			ENSP00000504612.1
ABCA1	ENST00000423487.6	c.303-39C>A		intron_variant	Intron 4 of 7	2		ENSP00000416623.2
ABCA1	ENST00000374733.1	c.123-39C>A		intron_variant	Intron 3 of 4	2		ENSP00000363865.1

Frequencies

GnomAD3 genomes AF: 0.0642 AC: 9762 AN: 152142 Hom.: 919 Cov.: 33

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0267

Gnomad ASJ AF: 0.0769

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.00434

Gnomad OTH AF: 0.0542

GnomAD2 exomes AF: 0.0222 AC: 5571 AN: 251306 AF XY: 0.0180

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.0175

Gnomad ASJ exome AF: 0.0700

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00481

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.0107 AC: 14786 AN: 1378628 Hom.: 925 Cov.: 23 AF XY: 0.00999 AC XY: 6899 AN XY: 690650

African (AFR) AF: 0.220 AC: 6990 AN: 31834

American (AMR) AF: 0.0182 AC: 811 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.0724 AC: 1857 AN: 25646

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39292

South Asian (SAS) AF: 0.00327 AC: 276 AN: 84492

European-Finnish (FIN) AF: 0.000338 AC: 18 AN: 53320

Middle Eastern (MID) AF: 0.0593 AC: 262 AN: 4418

European-Non Finnish (NFE) AF: 0.00309 AC: 3204 AN: 1037438

Other (OTH) AF: 0.0237 AC: 1367 AN: 57570

GnomAD4 genome AF: 0.0642 AC: 9769 AN: 152260 Hom.: 923 Cov.: 33 AF XY: 0.0609 AC XY: 4534 AN XY: 74446

African (AFR) AF: 0.208 AC: 8655 AN: 41524

American (AMR) AF: 0.0266 AC: 407 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0769 AC: 267 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.00434 AC: 295 AN: 68028

Other (OTH) AF: 0.0536 AC: 113 AN: 2108

Alfa AF: 0.0485 Hom.: 331

Bravo AF: 0.0738

Asia WGS AF: 0.0170 AC: 62 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 20, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	9.7
DANN	Benign	0.73
PhyloP100		2.3
Mutation Taster		=100/0	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: rs12003906; hg19: chr9-107645477;