chr9-104903458-G-A

Variant names:

• chr9-104903458-G-A
• rs2575876
• NM_005502.4:c.66+156C>T

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.66+156C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.238 in 152,056 control chromosomes in the GnomAD database, including 4,429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.24 (4429 hom., cov: 32)
• Consequence: ABCA1 NM_005502.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.05
• Publications: 52 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 9-104903458-G-A is Benign according to our data. Variant chr9-104903458-G-A is described in ClinVar as Benign. ClinVar VariationId is 1282893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.345 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.66+156C>T		intron	N/A	NP_005493.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	ENST00000374736.8	TSL:1 MANE Select	c.66+156C>T		intron	N/A	ENSP00000363868.3	O95477
	ABCA1	ENST00000678995.1		c.66+156C>T		intron	N/A	ENSP00000504612.1	A0A7I2V5U0
	ABCA1	ENST00000423487.6	TSL:2	c.66+156C>T		intron	N/A	ENSP00000416623.2	B1AMI2

Frequencies

GnomAD3 genomes AF: 0.238 AC: 36097 AN: 151938 Hom.: 4414 Cov.: 32

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.261

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.238 AC: 36142 AN: 152056 Hom.: 4429 Cov.: 32 AF XY: 0.236 AC XY: 17522 AN XY: 74320

African (AFR) AF: 0.204 AC: 8476 AN: 41464

American (AMR) AF: 0.268 AC: 4100 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 865 AN: 3470

East Asian (EAS) AF: 0.239 AC: 1234 AN: 5170

South Asian (SAS) AF: 0.359 AC: 1733 AN: 4828

European-Finnish (FIN) AF: 0.176 AC: 1860 AN: 10560

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 16974 AN: 67968

Other (OTH) AF: 0.267 AC: 565 AN: 2114

Alfa AF: 0.253 Hom.: 21875

Bravo AF: 0.242

Asia WGS AF: 0.322 AC: 1119 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.6
DANN	Benign	0.42
PhyloP100		-1.0
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: rs2575876; hg19: chr9-107665739; COSMIC: COSV66059984;