4-74770091-G-A

Position:

• chr4-74770091-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001729.4(BTC):​c.130C>T​(p.Leu44Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0053 in 1,613,172 control chromosomes in the GnomAD database, including 406 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.029 (220 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (186 hom.)
• Consequence: BTC NM_001729.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.51

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001920402).
• BP6: Variant 4-74770091-G-A is Benign according to our data. Variant chr4-74770091-G-A is described in ClinVar as [Benign]. Clinvar id is 780468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTC	NM_001729.4	c.130C>T	p.Leu44Phe	missense_variant	2/6	ENST00000395743.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTC	ENST00000395743.8	c.130C>T	p.Leu44Phe	missense_variant	2/6	1	NM_001729.4	P1
BTC	ENST00000512743.1	c.67C>T	p.Leu23Phe	missense_variant	1/4	5

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4356 AN: 152098 Hom.: 220 Cov.: 32

Gnomad AFR AF: 0.0997

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.00718 AC: 1800 AN: 250870 Hom.: 85 AF XY: 0.00521 AC XY: 707 AN XY: 135616

Gnomad AFR exome AF: 0.0999

Gnomad AMR exome AF: 0.00375

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000983

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00287 AC: 4190 AN: 1460956 Hom.: 186 Cov.: 30 AF XY: 0.00242 AC XY: 1762 AN XY: 726806

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.00428

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000142

Gnomad4 OTH exome AF: 0.00616

GnomAD4 genome AF: 0.0287 AC: 4364 AN: 152216 Hom.: 220 Cov.: 32 AF XY: 0.0276 AC XY: 2056 AN XY: 74422

Gnomad4 AFR AF: 0.0996

Gnomad4 AMR AF: 0.00975

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.00369 Hom.: 39

Bravo AF: 0.0331

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.102 AC: 450

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00919 AC: 1116

Asia WGS AF: 0.00491 AC: 18 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.035
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.037
Sift	Benign	0.082	T
Sift4G	Benign	0.11	T
Polyphen		0.99	D
Vest4		0.085
MVP		0.50
MPC		0.032
ClinPred		0.016	T
GERP RS		2.3
Varity_R		0.032
gMVP		0.56

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: rs56320257; hg19: chr4-75695301;