NM_018406.7:c.8223G>C

Variant names:

• chr3-195783357-C-G
• rs199812923
• NM_018406.7:c.8223G>C

Variant summary

Our verdict is Benign. The variant received -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. 13/19 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
• Publications: 10 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: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018406.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC4	NM_018406.7	MANE Select	c.8223G>C	p.Glu2741Asp	missense	Exon 2 of 25	NP_060876.5
	MUC4	NM_004532.6		c.83-4902G>C		intron	N/A	NP_004523.3
	MUC4	NM_138297.5		c.83-9052G>C		intron	N/A	NP_612154.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC4	ENST00000463781.8	TSL:5 MANE Select	c.8223G>C	p.Glu2741Asp	missense	Exon 2 of 25	ENSP00000417498.3
	MUC4	ENST00000346145.8	TSL:1	c.83-4902G>C		intron	N/A	ENSP00000304207.6
	MUC4	ENST00000349607.8	TSL:1	c.83-9052G>C		intron	N/A	ENSP00000338109.4

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

GnomAD2 exomes AF: 0.579 AC: 26311 AN: 45466 AF XY: 0.594

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 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

African (AFR) AF: 0.570 AC: 6848 AN: 12010

American (AMR) AF: 0.469 AC: 3559 AN: 7594

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 2154 AN: 5534

East Asian (EAS) AF: 0.339 AC: 3027 AN: 8926

South Asian (SAS) AF: 0.449 AC: 9019 AN: 20090

European-Finnish (FIN) AF: 0.538 AC: 5206 AN: 9672

Middle Eastern (MID) AF: 0.415 AC: 339 AN: 816

European-Non Finnish (NFE) AF: 0.227 AC: 52424 AN: 230662

Other (OTH) AF: 0.337 AC: 4463 AN: 13248

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

African (AFR) AF: 0.635 AC: 1746 AN: 2750

American (AMR) AF: 0.408 AC: 287 AN: 704

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 159 AN: 330

East Asian (EAS) AF: 0.419 AC: 129 AN: 308

South Asian (SAS) AF: 0.448 AC: 60 AN: 134

European-Finnish (FIN) AF: 0.443 AC: 227 AN: 512

Middle Eastern (MID) AF: 0.625 AC: 10 AN: 16

European-Non Finnish (NFE) AF: 0.429 AC: 1785 AN: 4164

Other (OTH) AF: 0.462 AC: 60 AN: 130

Alfa AF: 0.00 Hom.: 0

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

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: Does not pass quality filter, gene not related to pt phenotype

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
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
MetaRNN	Benign	0.000091	T
MetaSVM	Benign	-1.0	T
PhyloP100		-3.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.0060
Sift	Benign	1.0	T
Sift4G	Benign	0.54	T
Vest4		0.047
ClinPred		0.0035	T
GERP RS		-1.4
gMVP		0.000053
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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