chr3-195781795-G-GCC

Position:

• chr3-195781795-G-GCC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PVS1 BP6_Moderate

The NM_018406.7(MUC4):​c.9784_9785insGG​(p.Thr3262ArgfsTer998) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.057 (4 hom., cov: 0)
  • Exomes 𝑓: 0.18 (688 hom.)
  • Failed GnomAD Quality Control
• Consequence: MUC4 NM_018406.7 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.74

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 3-195781795-G-GCC is Benign according to our data. Variant chr3-195781795-G-GCC is described in ClinVar as [Benign]. Clinvar id is 403119.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC4	NM_018406.7	c.9784_9785insGG	p.Thr3262ArgfsTer998	frameshift_variant	2/25	ENST00000463781.8	NP_060876.5
MUC4	NM_004532.6	c.83-3341_83-3340insGG		intron_variant			NP_004523.3
MUC4	NM_138297.5	c.83-7491_83-7490insGG		intron_variant			NP_612154.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC4	ENST00000463781.8	c.9784_9785insGG	p.Thr3262ArgfsTer998	frameshift_variant	2/25	5	NM_018406.7	ENSP00000417498	A2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 4707 AN: 81870 Hom.: 4 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.0896

Gnomad AMR AF: 0.0529

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.0691

Gnomad FIN AF: 0.0569

Gnomad MID AF: 0.0220

Gnomad NFE AF: 0.0779

Gnomad OTH AF: 0.0492

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.180 AC: 153377 AN: 851190 Hom.: 688 Cov.: 25 AF XY: 0.176 AC XY: 72833 AN XY: 414898

Gnomad4 AFR exome AF: 0.0369

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.188

Gnomad4 EAS exome AF: 0.116

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.197

Gnomad4 OTH exome AF: 0.158

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0575 AC: 4709 AN: 81950 Hom.: 4 Cov.: 0 AF XY: 0.0568 AC XY: 2258 AN XY: 39742

Gnomad4 AFR AF: 0.0203

Gnomad4 AMR AF: 0.0529

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.0683

Gnomad4 FIN AF: 0.0569

Gnomad4 NFE AF: 0.0779

Gnomad4 OTH AF: 0.0508

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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: ExAC frequency -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs753854746; hg19: chr3-195508666;