rs4148337

Variant names:

• chr16-16014425-T-C
• rs4148337
• NM_004996.4:c.352-66T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004996.4(ABCC1):​c.352-66T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.667 in 1,563,264 control chromosomes in the GnomAD database, including 353,318 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.64 (31669 hom., cov: 32)
  • Exomes 𝑓: 0.67 (321649 hom.)
• Consequence: ABCC1 NM_004996.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.29
• Publications: 7 publications found

Genes affected

ABCC1 (HGNC:51): (ATP binding cassette subfamily C member 1 (ABCC1 blood group)) The 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 intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This full transporter is a member of the MRP subfamily which is involved in multi-drug resistance. This protein functions as a multispecific organic anion transporter, with oxidized glutatione, cysteinyl leukotrienes, and activated aflatoxin B1 as substrates. This protein also transports glucuronides and sulfate conjugates of steroid hormones and bile salts. Alternatively spliced variants of this gene have been described but their full-length nature is unknown. [provided by RefSeq, Apr 2012]

ABCC1 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
• hearing loss, autosomal dominant 77

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004996.4. 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
	ABCC1	NM_004996.4	MANE Select	c.352-66T>C		intron	N/A	NP_004987.2	P33527-1
	ABCC1	NM_019901.2		c.352-66T>C		intron	N/A	NP_063956.2
	ABCC1	NM_019902.2		c.352-66T>C		intron	N/A	NP_063957.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC1	ENST00000399410.8	TSL:1 MANE Select	c.352-66T>C		intron	N/A	ENSP00000382342.3	P33527-1
	ABCC1	ENST00000572882.3	TSL:1	c.352-66T>C		intron	N/A	ENSP00000461615.2	P33527-2
	ABCC1	ENST00000574224.2	TSL:1	n.427-66T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.640 AC: 97233 AN: 151896 Hom.: 31661 Cov.: 32

Gnomad AFR AF: 0.593

Gnomad AMI AF: 0.554

Gnomad AMR AF: 0.636

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.633

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.638

GnomAD4 exome AF: 0.670 AC: 945329 AN: 1411250 Hom.: 321649 AF XY: 0.666 AC XY: 465009 AN XY: 698418

African (AFR) AF: 0.590 AC: 18993 AN: 32218

American (AMR) AF: 0.572 AC: 22273 AN: 38930

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 15860 AN: 24340

East Asian (EAS) AF: 0.360 AC: 13949 AN: 38748

South Asian (SAS) AF: 0.482 AC: 38264 AN: 79464

European-Finnish (FIN) AF: 0.630 AC: 32427 AN: 51456

Middle Eastern (MID) AF: 0.618 AC: 2864 AN: 4638

European-Non Finnish (NFE) AF: 0.704 AC: 762747 AN: 1083212

Other (OTH) AF: 0.652 AC: 37952 AN: 58244

GnomAD4 genome AF: 0.640 AC: 97272 AN: 152014 Hom.: 31669 Cov.: 32 AF XY: 0.630 AC XY: 46800 AN XY: 74294

African (AFR) AF: 0.593 AC: 24562 AN: 41448

American (AMR) AF: 0.636 AC: 9703 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 2298 AN: 3472

East Asian (EAS) AF: 0.369 AC: 1907 AN: 5166

South Asian (SAS) AF: 0.468 AC: 2258 AN: 4822

European-Finnish (FIN) AF: 0.633 AC: 6680 AN: 10550

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.704 AC: 47866 AN: 67976

Other (OTH) AF: 0.632 AC: 1334 AN: 2112

Alfa AF: 0.673 Hom.: 4303

Bravo AF: 0.635

Asia WGS AF: 0.416 AC: 1452 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.11
DANN	Benign	0.69
PhyloP100		-1.3
BranchPoint Hunter		0.0
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: rs4148337; hg19: chr16-16108282; COSMIC: COSV60682511; COSMIC: COSV60682511;