NM_005502.4:c.2115+81A>G

Variant names:

• chr9-104828835-T-C
• rs10820738
• NM_005502.4:c.2115+81A>G

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.2115+81A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0667 in 1,419,262 control chromosomes in the GnomAD database, including 4,503 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (489 hom., cov: 33)
  • Exomes 𝑓: 0.067 (4014 hom.)
• Consequence: ABCA1 NM_005502.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.238
• Publications: 15 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=-0.91).
• BP6: Variant 9-104828835-T-C is Benign according to our data. Variant chr9-104828835-T-C is described in ClinVar as Benign. ClinVar VariationId is 1280071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.272 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	NM_005502.4	MANE Select	c.2115+81A>G		intron	N/A	NP_005493.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	ENST00000374736.8	TSL:1 MANE Select	c.2115+81A>G		intron	N/A	ENSP00000363868.3
	ABCA1	ENST00000678995.1		c.2115+81A>G		intron	N/A	ENSP00000504612.1
	ABCA1	ENST00000494467.1	TSL:3	n.288+81A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0637 AC: 9685 AN: 152154 Hom.: 486 Cov.: 33

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0978

Gnomad ASJ AF: 0.0991

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.0962

Gnomad FIN AF: 0.0466

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0577

Gnomad OTH AF: 0.0785

GnomAD4 exome AF: 0.0670 AC: 84914 AN: 1266990 Hom.: 4014 AF XY: 0.0679 AC XY: 43119 AN XY: 634934

African (AFR) AF: 0.0275 AC: 790 AN: 28694

American (AMR) AF: 0.123 AC: 4599 AN: 37486

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 2618 AN: 24484

East Asian (EAS) AF: 0.281 AC: 10019 AN: 35656

South Asian (SAS) AF: 0.0913 AC: 7102 AN: 77766

European-Finnish (FIN) AF: 0.0456 AC: 2195 AN: 48170

Middle Eastern (MID) AF: 0.0979 AC: 498 AN: 5086

European-Non Finnish (NFE) AF: 0.0553 AC: 52857 AN: 955624

Other (OTH) AF: 0.0784 AC: 4236 AN: 54024

GnomAD4 genome AF: 0.0637 AC: 9703 AN: 152272 Hom.: 489 Cov.: 33 AF XY: 0.0663 AC XY: 4938 AN XY: 74460

African (AFR) AF: 0.0298 AC: 1238 AN: 41562

American (AMR) AF: 0.0981 AC: 1500 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0991 AC: 344 AN: 3470

East Asian (EAS) AF: 0.284 AC: 1466 AN: 5166

South Asian (SAS) AF: 0.0963 AC: 465 AN: 4828

European-Finnish (FIN) AF: 0.0466 AC: 495 AN: 10620

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0576 AC: 3921 AN: 68018

Other (OTH) AF: 0.0839 AC: 177 AN: 2110

Alfa AF: 0.0614 Hom.: 111

Bravo AF: 0.0699

Asia WGS AF: 0.163 AC: 567 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 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.4
DANN	Benign	0.44
PhyloP100		-0.24
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: rs10820738; hg19: chr9-107591116; COSMIC: COSV66068421;