3-195779108-T-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.12472A>G(p.Thr4158Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 114,492 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 0.00017 (0 hom., cov: 25)
  • Exomes 𝑓: 0.000047 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: MUC4 NM_018406.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.45

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=0.0055555403).
• BP6: Variant 3-195779108-T-C is Benign according to our data. Variant chr3-195779108-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2654381.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.12472A>G	p.Thr4158Ala	missense_variant	2/25	ENST00000463781.8
MUC4	NM_004532.6	c.83-653A>G		intron_variant
MUC4	NM_138297.5	c.83-4803A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC4	ENST00000463781.8	c.12472A>G	p.Thr4158Ala	missense_variant	2/25	5	NM_018406.7	A2

Frequencies

GnomAD3 genomes AF: 0.000157 AC: 18 AN: 114396 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000174

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000544

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000206 AC: 30 AN: 145530 Hom.: 4 AF XY: 0.000194 AC XY: 15 AN XY: 77268

Gnomad AFR exome AF: 0.00241

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000634

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000467 AC: 63 AN: 1348340 Hom.: 3 Cov.: 154 AF XY: 0.0000466 AC XY: 31 AN XY: 665604

Gnomad4 AFR exome AF: 0.00130

Gnomad4 AMR exome AF: 0.0000877

Gnomad4 ASJ exome AF: 0.0000418

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.000127

GnomAD4 genome AF: 0.000175 AC: 20 AN: 114492 Hom.: 0 Cov.: 25 AF XY: 0.000196 AC XY: 11 AN XY: 56016

Gnomad4 AFR AF: 0.000534

Gnomad4 AMR AF: 0.000173

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000121

Gnomad4 NFE AF: 0.0000544

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000551 Hom.: 0

ExAC AF: 0.00181 AC: 92

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: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	2.7
Dann	Benign	0.36
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.47	T;T
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.015
Sift	Benign	0.093	T;T
Sift4G	Benign	0.30	T;T
Vest4		0.032
MVP		0.014
ClinPred		0.0076	T
gMVP		0.0048

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201251642; hg19: chr3-195505979; COSMIC: COSV57781454; COSMIC: COSV57781454;