dbSNP rs1104760: MUC4:p.Thr377Ile (chr3-195790450-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_018406.7(MUC4):c.1130C>T(p.Thr377Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.806 in 1,613,476 control chromosomes in the GnomAD database, including 526,927 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.80 ( 48996 hom., cov: 32)

Exomes 𝑓: 0.81 ( 477931 hom. )

Consequence

MUC4
NM_018406.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.373

Variant links:

Genes affected

MUC4 (HGNC:7514): (mucin 4, cell surface associated) The major constituents of mucus, the viscous secretion that covers epithelial surfaces such as those in the trachea, colon, and cervix, are highly glycosylated proteins called mucins. These glycoproteins play important roles in the protection of the epithelial cells and have been implicated in epithelial renewal and differentiation. This gene encodes an integral membrane glycoprotein found on the cell surface, although secreted isoforms may exist. At least two dozen transcript variants of this gene have been found, although for many of them the full-length transcript has not been determined or they are found only in tumor tissues. This gene contains a region in the coding sequence which has a variable number (>100) of 48 nt tandem repeats. [provided by RefSeq, Jul 2008]

MUC4 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.5415636E-6).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC4	NM_018406.7 link	c.1130C>T	p.Thr377Ile	missense_variant	Exon 2 of 25	ENST00000463781.8	NP_060876.5	Q99102-1E9PDY6
MUC4	NM_004532.6 link	c.83-11995C>T		intron_variant	Intron 1 of 23		NP_004523.3	Q99102-13A0T3F4
MUC4	NM_138297.5 link	c.83-16145C>T		intron_variant	Intron 1 of 22		NP_612154.2	Q99102-12A0T3F4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC4	ENST00000463781.8 link	c.1130C>T	p.Thr377Ile	missense_variant	Exon 2 of 25	5	NM_018406.7	ENSP00000417498.3		Q99102-1E9PDY6

Frequencies

GnomAD3 genomes

AF:

0.801

AC:

121729

AN:

152002

Hom.:

48958

Cov.:

show subpopulations

Gnomad AFR

AF:

0.815

Gnomad AMI

AF:

0.784

Gnomad AMR

AF:

0.712

Gnomad ASJ

AF:

0.845

Gnomad EAS

AF:

0.802

Gnomad SAS

AF:

0.676

Gnomad FIN

AF:

0.801

Gnomad MID

AF:

0.745

Gnomad NFE

AF:

0.818

Gnomad OTH

AF:

0.822

GnomAD3 exomes

AF:

0.775

AC:

193217

AN:

249256

Hom.:

75702

AF XY:

0.775

AC XY:

104857

AN XY:

135220

show subpopulations

Gnomad AFR exome

AF:

0.814

Gnomad AMR exome

AF:

0.633

Gnomad ASJ exome

AF:

0.841

Gnomad EAS exome

AF:

0.805

Gnomad SAS exome

AF:

0.664

Gnomad FIN exome

AF:

0.797

Gnomad NFE exome

AF:

0.828

Gnomad OTH exome

AF:

0.793

GnomAD4 exome

AF:

0.807

AC:

1178986

AN:

1461352

Hom.:

477931

Cov.:

AF XY:

0.804

AC XY:

584123

AN XY:

726972

show subpopulations

Gnomad4 AFR exome

AF:

0.815

Gnomad4 AMR exome

AF:

0.637

Gnomad4 ASJ exome

AF:

0.848

Gnomad4 EAS exome

AF:

0.813

Gnomad4 SAS exome

AF:

0.668

Gnomad4 FIN exome

AF:

0.792

Gnomad4 NFE exome

AF:

0.823

Gnomad4 OTH exome

AF:

0.811

GnomAD4 genome

AF:

0.801

AC:

121817

AN:

152124

Hom.:

48996

Cov.:

AF XY:

0.796

AC XY:

59232

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.815

Gnomad4 AMR

AF:

0.711

Gnomad4 ASJ

AF:

0.845

Gnomad4 EAS

AF:

0.802

Gnomad4 SAS

AF:

0.675

Gnomad4 FIN

AF:

0.801

Gnomad4 NFE

AF:

0.818

Gnomad4 OTH

AF:

0.824

Alfa

AF:

0.819

Hom.:

115531

Bravo

AF:

0.796

TwinsUK

AF:

0.827

AC:

3065

ALSPAC

AF:

0.824

AC:

3175

ESP6500AA

AF:

0.825

AC:

3228

ESP6500EA

AF:

0.824

AC:

6826

ExAC

AF:

0.780

AC:

94302

Asia WGS

AF:

0.807

AC:

2809

AN:

3478

EpiCase

AF:

0.833

EpiControl

AF:

0.838

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.20

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.44

T;T

MetaRNN

Benign

0.0000015

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

0.13

N;N

REVEL

Benign

0.018

Sift

Benign

1.0

T;T

Sift4G

Benign

0.35

T;T

Vest4

0.11

ClinPred

0.015

GERP RS

-0.91

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.014

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over