3-195779134-A-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_018406.7(MUC4):c.12446T>G(p.Ile4149Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 101,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 24)
  • Exomes 𝑓: 0.00022 (9 hom.)
  • Failed GnomAD Quality Control
• Consequence: MUC4 NM_018406.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.35

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042687654).
• BP6: Variant 3-195779134-A-C is Benign according to our data. Variant chr3-195779134-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2654382.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC4	NM_018406.7	c.12446T>G	p.Ile4149Ser	missense_variant	2/25	ENST00000463781.8
MUC4	NM_004532.6	c.83-679T>G		intron_variant
MUC4	NM_138297.5	c.83-4829T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC4	ENST00000463781.8	c.12446T>G	p.Ile4149Ser	missense_variant	2/25	5	NM_018406.7	A2

Frequencies

GnomAD3 genomes AF: 0.00100 AC: 102 AN: 101636 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.000778

Gnomad SAS AF: 0.000285

Gnomad FIN AF: 0.00111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000938

Gnomad OTH AF: 0.000761

GnomAD3 exomes AF: 0.000690 AC: 95 AN: 137668 Hom.: 4 AF XY: 0.000629 AC XY: 46 AN XY: 73182

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.000790

Gnomad ASJ exome AF: 0.000382

Gnomad EAS exome AF: 0.000233

Gnomad SAS exome AF: 0.000141

Gnomad FIN exome AF: 0.00132

Gnomad NFE exome AF: 0.000672

Gnomad OTH exome AF: 0.000260

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000218 AC: 274 AN: 1254720 Hom.: 9 Cov.: 153 AF XY: 0.000216 AC XY: 134 AN XY: 620090

Gnomad4 AFR exome AF: 0.00106

Gnomad4 AMR exome AF: 0.000376

Gnomad4 ASJ exome AF: 0.000225

Gnomad4 EAS exome AF: 0.000616

Gnomad4 SAS exome AF: 0.000203

Gnomad4 FIN exome AF: 0.000331

Gnomad4 NFE exome AF: 0.000172

Gnomad4 OTH exome AF: 0.000231

GnomAD4 genome AF: 0.00100 AC: 102 AN: 101722 Hom.: 0 Cov.: 24 AF XY: 0.000762 AC XY: 38 AN XY: 49868

Gnomad4 AFR AF: 0.00131

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.000780

Gnomad4 SAS AF: 0.000286

Gnomad4 FIN AF: 0.00111

Gnomad4 NFE AF: 0.000938

Gnomad4 OTH AF: 0.000752

ExAC AF: 0.00240 AC: 132

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

MUC4: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	1.1
Dann	Benign	0.45
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.56	T;T
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.77	N;N
REVEL	Benign	0.031
Sift	Benign	0.73	T;T
Sift4G	Benign	0.30	T;T
Vest4		0.080
MVP		0.048
ClinPred		0.0018	T
gMVP		0.0055

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs202017381; hg19: chr3-195506005; COSMIC: COSV57781458; COSMIC: COSV57781458;