rs2259292

Positions:

• chr3-195774278-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018406.7(MUC4):​c.12971G>A​(p.Gly4324Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 1,580,482 control chromosomes in the GnomAD database, including 261,628 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.58 (25712 hom., cov: 33)
  • Exomes 𝑓: 0.57 (235916 hom.)
• Consequence: MUC4 NM_018406.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.79

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.7244365E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.721 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC4	NM_018406.7	c.12971G>A	p.Gly4324Asp	missense_variant	4/25	ENST00000463781.8	NP_060876.5
MUC4	NM_004532.6	c.263G>A	p.Gly88Asp	missense_variant	3/24		NP_004523.3
MUC4	NM_138297.5	c.110G>A	p.Gly37Asp	missense_variant	2/23		NP_612154.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC4	ENST00000463781.8	c.12971G>A	p.Gly4324Asp	missense_variant	4/25	5	NM_018406.7	ENSP00000417498	A2

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87836 AN: 151932 Hom.: 25686 Cov.: 33

Gnomad AFR AF: 0.572

Gnomad AMI AF: 0.641

Gnomad AMR AF: 0.539

Gnomad ASJ AF: 0.659

Gnomad EAS AF: 0.741

Gnomad SAS AF: 0.525

Gnomad FIN AF: 0.618

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.588

GnomAD3 exomes AF: 0.588 AC: 129333 AN: 220020 Hom.: 38427 AF XY: 0.585 AC XY: 69858 AN XY: 119344

Gnomad AFR exome AF: 0.574

Gnomad AMR exome AF: 0.516

Gnomad ASJ exome AF: 0.674

Gnomad EAS exome AF: 0.747

Gnomad SAS exome AF: 0.514

Gnomad FIN exome AF: 0.622

Gnomad NFE exome AF: 0.590

Gnomad OTH exome AF: 0.591

GnomAD4 exome AF: 0.573 AC: 817814 AN: 1428432 Hom.: 235916 Cov.: 55 AF XY: 0.571 AC XY: 404878 AN XY: 709074

Gnomad4 AFR exome AF: 0.575

Gnomad4 AMR exome AF: 0.509

Gnomad4 ASJ exome AF: 0.668

Gnomad4 EAS exome AF: 0.729

Gnomad4 SAS exome AF: 0.501

Gnomad4 FIN exome AF: 0.608

Gnomad4 NFE exome AF: 0.570

Gnomad4 OTH exome AF: 0.582

GnomAD4 genome AF: 0.578 AC: 87904 AN: 152050 Hom.: 25712 Cov.: 33 AF XY: 0.577 AC XY: 42861 AN XY: 74336

Gnomad4 AFR AF: 0.573

Gnomad4 AMR AF: 0.539

Gnomad4 ASJ AF: 0.659

Gnomad4 EAS AF: 0.741

Gnomad4 SAS AF: 0.524

Gnomad4 FIN AF: 0.618

Gnomad4 NFE AF: 0.571

Gnomad4 OTH AF: 0.592

Alfa AF: 0.582 Hom.: 36335

Bravo AF: 0.570

TwinsUK AF: 0.561 AC: 2079

ALSPAC AF: 0.563 AC: 2169

ESP6500AA AF: 0.586 AC: 2582

ESP6500EA AF: 0.580 AC: 4991

ExAC AF: 0.576 AC: 69768

Asia WGS AF: 0.681 AC: 2368 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.60
DANN	Benign	0.82
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.055	T;T;T;T
MetaRNN	Benign	0.0000057	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.21	N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.67	T;T;T;T
Sift4G	Benign	0.47	T;T;T;T
Polyphen		0.0060	B;B;.;.
Vest4		0.21
ClinPred		0.0063	T
GERP RS		-2.1
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs2259292; hg19: chr3-195501149; COSMIC: COSV57772741; COSMIC: COSV57772741;