chr7-87443361-C-T

Variant names:

• chr7-87443361-C-T
• rs45624933
• NM_000443.4:c.1314G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000443.4(ABCB4):​c.1314G>A​(p.Thr438Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00494 in 1,614,046 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (19 hom.)
• Consequence: ABCB4 NM_000443.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -6.35
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 7-87443361-C-T is Benign according to our data. Variant chr7-87443361-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 281138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.35 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00461 (702/152198) while in subpopulation AMR AF = 0.0068 (104/15284). AF 95% confidence interval is 0.00575. There are 6 homozygotes in GnomAd4. There are 395 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 SD,AR,AD gene

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.1314G>A	p.Thr438Thr	synonymous	Exon 12 of 28	NP_000434.1	P21439-2
	ABCB4	NM_018849.3		c.1314G>A	p.Thr438Thr	synonymous	Exon 12 of 28	NP_061337.1	P21439-1
	ABCB4	NM_018850.3		c.1314G>A	p.Thr438Thr	synonymous	Exon 12 of 27	NP_061338.1	P21439-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB4	ENST00000649586.2	MANE Select	c.1314G>A	p.Thr438Thr	synonymous	Exon 12 of 28	ENSP00000496956.2	P21439-2
	ABCB4	ENST00000265723.8	TSL:1	c.1314G>A	p.Thr438Thr	synonymous	Exon 12 of 28	ENSP00000265723.4	P21439-1
	ABCB4	ENST00000359206.8	TSL:1	c.1314G>A	p.Thr438Thr	synonymous	Exon 12 of 28	ENSP00000352135.3	P21439-2

Frequencies

GnomAD3 genomes AF: 0.00462 AC: 702 AN: 152080 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0169

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00435

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00463 AC: 1164 AN: 251350 AF XY: 0.00462

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00280

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.00590

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00497 AC: 7268 AN: 1461848 Hom.: 19 Cov.: 32 AF XY: 0.00481 AC XY: 3499 AN XY: 727234

African (AFR) AF: 0.00242 AC: 81 AN: 33478

American (AMR) AF: 0.00286 AC: 128 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0158 AC: 844 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00538 AC: 5987 AN: 1111984

Other (OTH) AF: 0.00374 AC: 226 AN: 60396

GnomAD4 genome AF: 0.00461 AC: 702 AN: 152198 Hom.: 6 Cov.: 32 AF XY: 0.00531 AC XY: 395 AN XY: 74396

African (AFR) AF: 0.00270 AC: 112 AN: 41524

American (AMR) AF: 0.00680 AC: 104 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0169 AC: 179 AN: 10588

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00435 AC: 296 AN: 68018

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00378 Hom.: 3

Bravo AF: 0.00366

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00492

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (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	-0.70
CADD	Benign	0.025
DANN	Benign	0.59
PhyloP100		-6.3
Mutation Taster		=99/1	polymorphism

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: rs45624933; hg19: chr7-87072677;