9-104826853-A-T

Variant names:

• chr9-104826853-A-T
• rs4149310
• NM_005502.4:c.2337+95T>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.2337+95T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,164,744 control chromosomes in the GnomAD database, including 43,346 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (13256 hom., cov: 33)
  • Exomes 𝑓: 0.20 (30090 hom.)
• Consequence: ABCA1 NM_005502.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.360
• Publications: 24 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=-0.94).
• BP6: Variant 9-104826853-A-T is Benign according to our data. Variant chr9-104826853-A-T is described in ClinVar as Benign. ClinVar VariationId is 1177848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.696 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.2337+95T>A		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.2337+95T>A		intron	N/A	ENSP00000363868.3
	ABCA1	ENST00000678995.1		c.2337+95T>A		intron	N/A	ENSP00000504612.1
	ABCA1	ENST00000494467.1	TSL:3	n.510+95T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52129 AN: 152042 Hom.: 13212 Cov.: 33

Gnomad AFR AF: 0.683

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.716

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.339

GnomAD4 exome AF: 0.202 AC: 204968 AN: 1012584 Hom.: 30090 AF XY: 0.201 AC XY: 104220 AN XY: 519276

African (AFR) AF: 0.686 AC: 16334 AN: 23794

American (AMR) AF: 0.358 AC: 13443 AN: 37540

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 5634 AN: 22896

East Asian (EAS) AF: 0.701 AC: 24556 AN: 35030

South Asian (SAS) AF: 0.212 AC: 15436 AN: 72784

European-Finnish (FIN) AF: 0.112 AC: 5152 AN: 45994

Middle Eastern (MID) AF: 0.299 AC: 991 AN: 3312

European-Non Finnish (NFE) AF: 0.155 AC: 112119 AN: 725608

Other (OTH) AF: 0.248 AC: 11303 AN: 45626

GnomAD4 genome AF: 0.343 AC: 52233 AN: 152160 Hom.: 13256 Cov.: 33 AF XY: 0.342 AC XY: 25426 AN XY: 74402

African (AFR) AF: 0.683 AC: 28338 AN: 41476

American (AMR) AF: 0.337 AC: 5155 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 833 AN: 3460

East Asian (EAS) AF: 0.716 AC: 3698 AN: 5168

South Asian (SAS) AF: 0.223 AC: 1079 AN: 4830

European-Finnish (FIN) AF: 0.117 AC: 1242 AN: 10606

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10846 AN: 68006

Other (OTH) AF: 0.343 AC: 724 AN: 2112

Alfa AF: 0.240 Hom.: 1073

Bravo AF: 0.381

Asia WGS AF: 0.473 AC: 1644 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

Aug 30, 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	-0.94
CADD	Benign	1.3
DANN	Benign	0.56
PhyloP100		-0.36
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: rs4149310; hg19: chr9-107589134; COSMIC: COSV66071138;