3-195783357-C-G

Position:

• chr3-195783357-C-G

Variant summary

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

The NM_018406.7(MUC4):​c.8223G>C​(p.Glu2741Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (1009 hom., cov: 0)
  • Exomes 𝑓: 0.28 (17649 hom.)
  • Failed GnomAD Quality Control
• Consequence: MUC4 NM_018406.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.54

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.061409E-5).
• BP6: Variant 3-195783357-C-G is Benign according to our data. Variant chr3-195783357-C-G is described in ClinVar as [Benign]. Clinvar id is 403121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC4	NM_018406.7	c.8223G>C	p.Glu2741Asp	missense_variant	2/25	ENST00000463781.8	NP_060876.5
MUC4	NM_004532.6	c.83-4902G>C		intron_variant			NP_004523.3
MUC4	NM_138297.5	c.83-9052G>C		intron_variant			NP_612154.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC4	ENST00000463781.8	c.8223G>C	p.Glu2741Asp	missense_variant	2/25	5	NM_018406.7	ENSP00000417498	A2

Frequencies

GnomAD3 genomes AF: 0.493 AC: 4482 AN: 9094 Hom.: 1011 Cov.: 0

Gnomad AFR AF: 0.636

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.625

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.462

GnomAD3 exomes AF: 0.579 AC: 26311 AN: 45466 Hom.: 6507 AF XY: 0.594 AC XY: 14103 AN XY: 23748

Gnomad AFR exome AF: 0.650

Gnomad AMR exome AF: 0.592

Gnomad ASJ exome AF: 0.646

Gnomad EAS exome AF: 0.537

Gnomad SAS exome AF: 0.670

Gnomad FIN exome AF: 0.486

Gnomad NFE exome AF: 0.575

Gnomad OTH exome AF: 0.590

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.282 AC: 87039 AN: 308552 Hom.: 17649 Cov.: 8 AF XY: 0.298 AC XY: 45683 AN XY: 153286

Gnomad4 AFR exome AF: 0.570

Gnomad4 AMR exome AF: 0.469

Gnomad4 ASJ exome AF: 0.389

Gnomad4 EAS exome AF: 0.339

Gnomad4 SAS exome AF: 0.449

Gnomad4 FIN exome AF: 0.538

Gnomad4 NFE exome AF: 0.227

Gnomad4 OTH exome AF: 0.337

GnomAD4 genome AF: 0.492 AC: 4483 AN: 9106 Hom.: 1009 Cov.: 0 AF XY: 0.481 AC XY: 2064 AN XY: 4292

Gnomad4 AFR AF: 0.635

Gnomad4 AMR AF: 0.408

Gnomad4 ASJ AF: 0.482

Gnomad4 EAS AF: 0.419

Gnomad4 SAS AF: 0.448

Gnomad4 FIN AF: 0.443

Gnomad4 NFE AF: 0.429

Gnomad4 OTH AF: 0.462

ExAC AF: 0.522 AC: 10034

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Does not pass quality filter, gene not related to pt phenotype -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.19
DANN	Benign	0.28
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.00034	N
LIST_S2	Benign	0.52	T;T
MetaRNN	Benign	0.000091	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.27	N;N
REVEL	Benign	0.0060
Sift	Benign	1.0	T;T
Sift4G	Benign	0.54	T;T
Vest4		0.047
ClinPred		0.0035	T
GERP RS		-1.4
gMVP		0.000053

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: rs199812923; hg19: chr3-195510228; COSMIC: COSV57766637; COSMIC: COSV57766637;