Genetic Variant MUC4:p.Ser1960* (chr3-195785701-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018406.7(MUC4):c.5879C>A(p.Ser1960*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 50)

Exomes 𝑓: 0.0000040 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MUC4
NM_018406.7 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.02

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MUC4	NM_018406.7	MANE Select	c.5879C>A	p.Ser1960*	stop_gained	Exon 2 of 25	NP_060876.5
MUC4	NM_004532.6		c.83-7246C>A		intron	N/A	NP_004523.3
MUC4	NM_138297.5		c.83-11396C>A		intron	N/A	NP_612154.2	Q99102-12

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MUC4	ENST00000463781.8	TSL:5 MANE Select	c.5879C>A	p.Ser1960*	stop_gained	Exon 2 of 25	ENSP00000417498.3	Q99102-1
MUC4	ENST00000346145.8	TSL:1	c.83-7246C>A		intron	N/A	ENSP00000304207.6	Q99102-13
MUC4	ENST00000349607.8	TSL:1	c.83-11396C>A		intron	N/A	ENSP00000338109.4	Q99102-12

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

161004

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000397

AC:

AN:

1260426

Hom.:

Cov.:

251

AF XY:

0.00000482

AC XY:

AN XY:

622928

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

28184

American (AMR)

AF:

0.00

AC:

AN:

30490

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21164

East Asian (EAS)

AF:

0.00

AC:

AN:

30324

South Asian (SAS)

AF:

0.00

AC:

AN:

72574

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3954

European-Non Finnish (NFE)

AF:

0.00000512

AC:

AN:

977104

Other (OTH)

AF:

0.00

AC:

AN:

51312

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.255

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Benign

0.96

Eigen

Benign

-0.028

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.0061

PhyloP100

1.0

Vest4

0.051

GERP RS

-0.041

Mutation Taster

=198/2

disease causing (fs/PTC)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over