9-104830901-A-T

Variant names:

• chr9-104830901-A-T
• rs4743763
• NM_005502.4:c.1892+24T>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.1892+24T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 1,612,060 control chromosomes in the GnomAD database, including 96,459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (18514 hom., cov: 29)
  • Exomes 𝑓: 0.30 (77945 hom.)
• Consequence: ABCA1 NM_005502.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.917
• 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=-0.85).
• BP6: Variant 9-104830901-A-T is Benign according to our data. Variant chr9-104830901-A-T is described in ClinVar as Benign. ClinVar VariationId is 1232269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA1	NM_005502.4	c.1892+24T>A		intron_variant	Intron 14 of 49	ENST00000374736.8	NP_005493.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA1	ENST00000374736.8	c.1892+24T>A		intron_variant	Intron 14 of 49	1	NM_005502.4	ENSP00000363868.3
ABCA1	ENST00000678995.1	c.1892+24T>A		intron_variant	Intron 14 of 49			ENSP00000504612.1
ABCA1	ENST00000494467.1	n.65+24T>A		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66176 AN: 151468 Hom.: 18454 Cov.: 29

Gnomad AFR AF: 0.767

Gnomad AMI AF: 0.448

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.795

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.214

Gnomad MID AF: 0.439

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.428

GnomAD2 exomes AF: 0.363 AC: 91232 AN: 251440 AF XY: 0.348

Gnomad AFR exome AF: 0.773

Gnomad AMR exome AF: 0.406

Gnomad ASJ exome AF: 0.327

Gnomad EAS exome AF: 0.808

Gnomad FIN exome AF: 0.206

Gnomad NFE exome AF: 0.269

Gnomad OTH exome AF: 0.348

GnomAD4 exome AF: 0.302 AC: 441259 AN: 1460474 Hom.: 77945 Cov.: 34 AF XY: 0.301 AC XY: 218660 AN XY: 726622

African (AFR) AF: 0.787 AC: 26332 AN: 33444

American (AMR) AF: 0.407 AC: 18200 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 8628 AN: 26130

East Asian (EAS) AF: 0.800 AC: 31748 AN: 39678

South Asian (SAS) AF: 0.306 AC: 26350 AN: 86176

European-Finnish (FIN) AF: 0.205 AC: 10936 AN: 53368

Middle Eastern (MID) AF: 0.420 AC: 2371 AN: 5648

European-Non Finnish (NFE) AF: 0.266 AC: 295770 AN: 1110998

Other (OTH) AF: 0.347 AC: 20924 AN: 60320

GnomAD4 genome AF: 0.437 AC: 66295 AN: 151586 Hom.: 18514 Cov.: 29 AF XY: 0.435 AC XY: 32180 AN XY: 74046

African (AFR) AF: 0.768 AC: 31718 AN: 41324

American (AMR) AF: 0.404 AC: 6149 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1106 AN: 3466

East Asian (EAS) AF: 0.794 AC: 4071 AN: 5128

South Asian (SAS) AF: 0.317 AC: 1516 AN: 4776

European-Finnish (FIN) AF: 0.214 AC: 2252 AN: 10512

Middle Eastern (MID) AF: 0.432 AC: 126 AN: 292

European-Non Finnish (NFE) AF: 0.266 AC: 18039 AN: 67850

Other (OTH) AF: 0.434 AC: 909 AN: 2094

Alfa AF: 0.333 Hom.: 1911

Bravo AF: 0.471

Asia WGS AF: 0.584 AC: 2029 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.3
DANN	Benign	0.66
PhyloP100		0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs4743763; hg19: chr9-107593182; COSMIC: COSV66069377;