3-195781795-G-GCC

Variant names:

• chr3-195781795-G-GCC
• rs753854746
• NM_018406.7:c.9784_9785insGG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. 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
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• 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 rank	MANE	Protein	UniProt
MUC4	NM_018406.7	c.9784_9785insGG	p.Thr3262ArgfsTer998	frameshift_variant	Exon 2 of 25	ENST00000463781.8	NP_060876.5
MUC4	NM_004532.6	c.83-3341_83-3340insGG		intron_variant	Intron 1 of 23		NP_004523.3
MUC4	NM_138297.5	c.83-7491_83-7490insGG		intron_variant	Intron 1 of 22		NP_612154.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC4	ENST00000463781.8	c.9784_9785insGG	p.Thr3262ArgfsTer998	frameshift_variant	Exon 2 of 25	5	NM_018406.7	ENSP00000417498.3

Frequencies

GnomAD3 genomes AF: 0.0575 AC: 4707 AN: 81870 Hom.: 4 Cov.: 0

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

GnomAD2 exomes AF: 0.0241 AC: 3329 AN: 137916 AF XY: 0.0232

Gnomad AFR exome AF: 0.00613

Gnomad AMR exome AF: 0.0154

Gnomad ASJ exome AF: 0.0258

Gnomad EAS exome AF: 0.00942

Gnomad FIN exome AF: 0.0586

Gnomad NFE exome AF: 0.0260

Gnomad OTH exome AF: 0.0204

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0369 AC: 881 AN: 23868

American (AMR) AF: 0.108 AC: 2509 AN: 23168

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 2335 AN: 12438

East Asian (EAS) AF: 0.116 AC: 1117 AN: 9594

South Asian (SAS) AF: 0.104 AC: 4872 AN: 46630

European-Finnish (FIN) AF: 0.108 AC: 1963 AN: 18144

Middle Eastern (MID) AF: 0.122 AC: 293 AN: 2406

European-Non Finnish (NFE) AF: 0.197 AC: 134252 AN: 682402

Other (OTH) AF: 0.158 AC: 5155 AN: 32540

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0203 AC: 504 AN: 24812

American (AMR) AF: 0.0529 AC: 424 AN: 8008

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 164 AN: 1534

East Asian (EAS) AF: 0.109 AC: 278 AN: 2542

South Asian (SAS) AF: 0.0683 AC: 181 AN: 2650

European-Finnish (FIN) AF: 0.0569 AC: 308 AN: 5414

Middle Eastern (MID) AF: 0.0233 AC: 4 AN: 172

European-Non Finnish (NFE) AF: 0.0779 AC: 2749 AN: 35292

Other (OTH) AF: 0.0508 AC: 52 AN: 1024

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.7
Mutation Taster		=200/0	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs753854746; hg19: chr3-195508666;