4-74755887-C-T

Variant names:

• chr4-74755887-C-T
• rs367987587
• NM_001729.4:c.253G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001729.4(BTC):​c.253G>A​(p.Val85Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: BTC NM_001729.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22
• Publications: 0 publications found

Genes affected

BTC (HGNC:1121): (betacellulin) This gene encodes a member of the epidermal growth factor (EGF) family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the secreted growth factor. A secreted form and a membrane-anchored form of this protein bind to multiple different EGF receptors. This protein promotes pancreatic cell proliferation and insulin secretion, as well as retinal vascular permeability. Mutations in this gene may be associated with type 2 diabetes in human patients. [provided by RefSeq, Nov 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38850164).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001729.4. 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
	BTC	NM_001729.4	MANE Select	c.253G>A	p.Val85Met	missense	Exon 3 of 6	NP_001720.1	A0A0S2Z437
	BTC	NM_001316963.2		c.253G>A	p.Val85Met	missense	Exon 3 of 5	NP_001303892.1	A0A0S2Z3I5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTC	ENST00000395743.8	TSL:1 MANE Select	c.253G>A	p.Val85Met	missense	Exon 3 of 6	ENSP00000379092.3	P35070
	BTC	ENST00000909121.1		c.253G>A	p.Val85Met	missense	Exon 3 of 6	ENSP00000579180.1
	BTC	ENST00000909122.1		c.253G>A	p.Val85Met	missense	Exon 3 of 5	ENSP00000579181.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000278 AC: 7 AN: 251416 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111990

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74460

African (AFR) AF: 0.0000722 AC: 3 AN: 41534

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.20
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.50
MVP		0.72
MPC		0.18
ClinPred		0.30	T
GERP RS		3.8
Varity_R		0.072
gMVP		0.68
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs367987587; hg19: chr4-75681097; COSMIC: COSV67547769;