NM_004996.4:c.3591-5C>T

Variant names:

• chr16-16124784-C-T
• rs41278168
• NM_004996.4:c.3591-5C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004996.4(ABCC1):​c.3591-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,613,990 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (5 hom.)
• Consequence: ABCC1 NM_004996.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001609
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.812
• Publications: 2 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):

• hearing loss, autosomal dominant 77

  Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-16124784-C-T is Benign according to our data. Variant chr16-16124784-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 711596.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 192 AD,Unknown gene.

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.3591-5C>T		splice_region intron	N/A	NP_004987.2
	ABCC1	NM_019901.2		c.3465-5C>T		splice_region intron	N/A	NP_063956.2
	ABCC1	NM_019902.2		c.3444-5C>T		splice_region 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.3591-5C>T		splice_region intron	N/A	ENSP00000382342.3
	ABCC1	ENST00000572882.3	TSL:1	c.3414-5C>T		splice_region intron	N/A	ENSP00000461615.2
	ABCC1	ENST00000914156.1		c.3747-5C>T		splice_region intron	N/A	ENSP00000584215.1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00196

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000970 AC: 242 AN: 249418 AF XY: 0.000917

Gnomad AFR exome AF: 0.00116

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000511

Gnomad NFE exome AF: 0.00176

Gnomad OTH exome AF: 0.000989

GnomAD4 exome AF: 0.00164 AC: 2401 AN: 1461722 Hom.: 5 Cov.: 31 AF XY: 0.00162 AC XY: 1175 AN XY: 727162

African (AFR) AF: 0.000747 AC: 25 AN: 33478

American (AMR) AF: 0.000268 AC: 12 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26136

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86244

European-Finnish (FIN) AF: 0.000600 AC: 32 AN: 53360

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5692

European-Non Finnish (NFE) AF: 0.00202 AC: 2249 AN: 1112008

Other (OTH) AF: 0.000977 AC: 59 AN: 60380

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000940 AC XY: 70 AN XY: 74440

African (AFR) AF: 0.000963 AC: 40 AN: 41552

American (AMR) AF: 0.000196 AC: 3 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00196 AC: 133 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00148 Hom.: 1

Bravo AF: 0.00124

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00178

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.010
DANN	Benign	0.64
PhyloP100		-0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0080
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: rs41278168; hg19: chr16-16218641;