7-87450090-T-C

Variant names:

• chr7-87450090-T-C
• rs2109505
• NM_000443.4:c.711A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000443.4(ABCB4):​c.711A>G​(p.Ile237Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I237I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCB4 NM_000443.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.477

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ABCB4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 1.9749 (below the threshold of 3.09). Trascript score misZ: 3.5425 (above the threshold of 3.09). GenCC associations: The gene is linked to pancreatitis, low phospholipid associated cholelithiasis, progressive familial intrahepatic cholestasis type 3.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3483156).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB4	NM_000443.4	c.711A>G	p.Ile237Met	missense_variant, splice_region_variant	Exon 8 of 28	ENST00000649586.2	NP_000434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB4	ENST00000649586.2	c.711A>G	p.Ile237Met	missense_variant, splice_region_variant	Exon 8 of 28		NM_000443.4	ENSP00000496956.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.0086	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	.;.;T;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.81	.;T;T;T;.
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.35	T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.8	L;L;L;L;L
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.1	.;N;N;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.26	.;T;T;T;T
Sift4G	Benign	0.55	.;T;T;T;T
Polyphen		0.84	P;.;P;P;.
Vest4		0.39, 0.31, 0.31, 0.39
MutPred		0.46		Gain of catalytic residue at I237 (P = 0.0166);Gain of catalytic residue at I237 (P = 0.0166);Gain of catalytic residue at I237 (P = 0.0166);Gain of catalytic residue at I237 (P = 0.0166);Gain of catalytic residue at I237 (P = 0.0166);
MVP		0.79
MPC		0.35
ClinPred		0.43	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs2109505; hg19: chr7-87079406;