rs31653

Variant names:

• chr7-87403297-A-G
• rs31653
• NM_000443.4:c.3487-16T>C

Your query was ambiguous. Multiple possible variants found:

• chr7-87403297-A-G
• chr7-87403297-A-C
• chr7-87403297-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000443.4(ABCB4):​c.3487-16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.889 in 1,610,832 control chromosomes in the GnomAD database, including 638,677 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.91 (63373 hom., cov: 31)
  • Exomes 𝑓: 0.89 (575304 hom.)
• Consequence: ABCB4 NM_000443.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.45
• Publications: 18 publications found

Genes affected

ABCB4 (HGNC:45): (ATP binding cassette subfamily B member 4) 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 intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance as well as antigen presentation. This gene encodes a full transporter and member of the p-glycoprotein family of membrane proteins with phosphatidylcholine as its substrate. The function of this protein has not yet been determined; however, it may involve transport of phospholipids from liver hepatocytes into bile. Alternative splicing of this gene results in several products of undetermined function. [provided by RefSeq, Jul 2008]

ABCB4 Gene-Disease associations (from GenCC):

• progressive familial intrahepatic cholestasis type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• gallbladder disease 1

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-87403297-A-G is Benign according to our data. Variant chr7-87403297-A-G is described in ClinVar as Benign. ClinVar VariationId is 256164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000443.4. 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
	ABCB4	NM_000443.4	MANE Select	c.3487-16T>C		intron	N/A	NP_000434.1	P21439-2
	ABCB4	NM_018849.3		c.3508-16T>C		intron	N/A	NP_061337.1	P21439-1
	ABCB4	NM_018850.3		c.3346-16T>C		intron	N/A	NP_061338.1	P21439-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB4	ENST00000649586.2	MANE Select	c.3487-16T>C		intron	N/A	ENSP00000496956.2	P21439-2
	ABCB4	ENST00000265723.8	TSL:1	c.3508-16T>C		intron	N/A	ENSP00000265723.4	P21439-1
	ABCB4	ENST00000359206.8	TSL:1	c.3487-16T>C		intron	N/A	ENSP00000352135.3	P21439-2

Frequencies

GnomAD3 genomes AF: 0.910 AC: 138494 AN: 152124 Hom.: 63323 Cov.: 31

Gnomad AFR AF: 0.976

Gnomad AMI AF: 0.951

Gnomad AMR AF: 0.899

Gnomad ASJ AF: 0.904

Gnomad EAS AF: 0.717

Gnomad SAS AF: 0.887

Gnomad FIN AF: 0.867

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.896

Gnomad OTH AF: 0.913

GnomAD2 exomes AF: 0.874 AC: 219633 AN: 251332 AF XY: 0.876

Gnomad AFR exome AF: 0.978

Gnomad AMR exome AF: 0.817

Gnomad ASJ exome AF: 0.908

Gnomad EAS exome AF: 0.716

Gnomad FIN exome AF: 0.863

Gnomad NFE exome AF: 0.896

Gnomad OTH exome AF: 0.888

GnomAD4 exome AF: 0.887 AC: 1293859 AN: 1458590 Hom.: 575304 Cov.: 34 AF XY: 0.887 AC XY: 644000 AN XY: 725884

African (AFR) AF: 0.979 AC: 32708 AN: 33416

American (AMR) AF: 0.825 AC: 36882 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.906 AC: 23661 AN: 26108

East Asian (EAS) AF: 0.696 AC: 27612 AN: 39668

South Asian (SAS) AF: 0.892 AC: 76892 AN: 86202

European-Finnish (FIN) AF: 0.865 AC: 46184 AN: 53410

Middle Eastern (MID) AF: 0.925 AC: 5265 AN: 5690

European-Non Finnish (NFE) AF: 0.894 AC: 991188 AN: 1109112

Other (OTH) AF: 0.887 AC: 53467 AN: 60266

GnomAD4 genome AF: 0.910 AC: 138603 AN: 152242 Hom.: 63373 Cov.: 31 AF XY: 0.909 AC XY: 67640 AN XY: 74444

African (AFR) AF: 0.976 AC: 40564 AN: 41562

American (AMR) AF: 0.899 AC: 13752 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.904 AC: 3136 AN: 3470

East Asian (EAS) AF: 0.717 AC: 3709 AN: 5170

South Asian (SAS) AF: 0.887 AC: 4266 AN: 4810

European-Finnish (FIN) AF: 0.867 AC: 9192 AN: 10602

Middle Eastern (MID) AF: 0.942 AC: 277 AN: 294

European-Non Finnish (NFE) AF: 0.896 AC: 60914 AN: 68014

Other (OTH) AF: 0.911 AC: 1926 AN: 2114

Alfa AF: 0.900 Hom.: 105439

Bravo AF: 0.912

Asia WGS AF: 0.812 AC: 2825 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Cholestasis, intrahepatic, of pregnancy, 3 (1)
-	-	1	Progressive familial intrahepatic cholestasis type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.83
DANN	Benign	0.47
PhyloP100		-1.4
PromoterAI		0.013	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 43

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs31653; hg19: chr7-87032613; COSMIC: COSV55935709; COSMIC: COSV55935709;