3-195784460-A-C

Variant names:

• chr3-195784460-A-C
• rs56359992
• NM_018406.7:c.7120T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018406.7(MUC4):​c.7120T>G​(p.Ser2374Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000234 in 642,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2374P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000077 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: MUC4 NM_018406.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.08
• Publications: 17 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02857703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC4	NM_018406.7	c.7120T>G	p.Ser2374Ala	missense_variant	Exon 2 of 25	ENST00000463781.8	NP_060876.5
MUC4	NM_004532.6	c.83-6005T>G		intron_variant	Intron 1 of 23		NP_004523.3
MUC4	NM_138297.5	c.83-10155T>G		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.7120T>G	p.Ser2374Ala	missense_variant	Exon 2 of 25	5	NM_018406.7	ENSP00000417498.3

Frequencies

GnomAD3 genomes AF: 0.0000774 AC: 5 AN: 64562 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000216

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000339

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000173 AC: 10 AN: 577466 Hom.: 0 Cov.: 295 AF XY: 0.00000714 AC XY: 2 AN XY: 279946

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

African (AFR) AF: 0.000206 AC: 2 AN: 9692

American (AMR) AF: 0.000117 AC: 1 AN: 8568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6522

East Asian (EAS) AF: 0.00 AC: 0 AN: 4588

South Asian (SAS) AF: 0.0000352 AC: 1 AN: 28396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2318

European-Non Finnish (NFE) AF: 0.0000123 AC: 6 AN: 487318

Other (OTH) AF: 0.00 AC: 0 AN: 20762

⚠️ 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 AF: 0.0000774 AC: 5 AN: 64562 Hom.: 0 Cov.: 0 AF XY: 0.0000961 AC XY: 3 AN XY: 31218

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

African (AFR) AF: 0.000216 AC: 4 AN: 18484

American (AMR) AF: 0.00 AC: 0 AN: 6052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1260

East Asian (EAS) AF: 0.00 AC: 0 AN: 1714

South Asian (SAS) AF: 0.00 AC: 0 AN: 2208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 178

European-Non Finnish (NFE) AF: 0.0000339 AC: 1 AN: 29502

Other (OTH) AF: 0.00 AC: 0 AN: 894

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.003998), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 6564

ExAC AF: 0.0000324 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.2
DANN	Benign	0.35
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.00036	N
LIST_S2	Benign	0.32	T;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.029	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.35	N;N
REVEL	Benign	0.015
Sift	Benign	0.30	T;T
Sift4G	Benign	0.15	T;T
Vest4		0.090
MutPred		0.25		Loss of glycosylation at S2374 (P = 0.0018);Loss of glycosylation at S2374 (P = 0.0018);
MVP		0.014
ClinPred		0.089	T
gMVP		0.00039
Mutation Taster		=100/0	polymorphism

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: rs56359992; hg19: chr3-195511331;