rs2246901

Positions:

• chr3-195762138-C-A
• chr3-195762138-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.14461G>T​(p.Ala4821Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.694 in 1,605,570 control chromosomes in the GnomAD database, including 390,638 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 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 0.64 (31635 hom., cov: 31)
  • Exomes 𝑓: 0.70 (359003 hom.)
• Consequence: MUC4 NM_018406.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.225

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=1.5529344E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC4	NM_018406.7	c.14461G>T	p.Ala4821Ser	missense_variant	14/25	ENST00000463781.8	NP_060876.5
MUC4	NM_004532.6	c.1753G>T	p.Ala585Ser	missense_variant	13/24		NP_004523.3
MUC4	NM_138297.5	c.1600G>T	p.Ala534Ser	missense_variant	12/23		NP_612154.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC4	ENST00000463781.8	c.14461G>T	p.Ala4821Ser	missense_variant	14/25	5	NM_018406.7	ENSP00000417498.3

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96273 AN: 151510 Hom.: 31619 Cov.: 31

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.714

Gnomad AMR AF: 0.570

Gnomad ASJ AF: 0.761

Gnomad EAS AF: 0.804

Gnomad SAS AF: 0.608

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.647

GnomAD3 exomes AF: 0.669 AC: 156833 AN: 234370 Hom.: 53502 AF XY: 0.671 AC XY: 85731 AN XY: 127686

Gnomad AFR exome AF: 0.483

Gnomad AMR exome AF: 0.552

Gnomad ASJ exome AF: 0.741

Gnomad EAS exome AF: 0.807

Gnomad SAS exome AF: 0.594

Gnomad FIN exome AF: 0.704

Gnomad NFE exome AF: 0.717

Gnomad OTH exome AF: 0.679

GnomAD4 exome AF: 0.700 AC: 1017224 AN: 1453942 Hom.: 359003 Cov.: 72 AF XY: 0.698 AC XY: 504466 AN XY: 722850

Gnomad4 AFR exome AF: 0.478

Gnomad4 AMR exome AF: 0.555

Gnomad4 ASJ exome AF: 0.753

Gnomad4 EAS exome AF: 0.816

Gnomad4 SAS exome AF: 0.600

Gnomad4 FIN exome AF: 0.699

Gnomad4 NFE exome AF: 0.715

Gnomad4 OTH exome AF: 0.697

GnomAD4 genome AF: 0.635 AC: 96329 AN: 151628 Hom.: 31635 Cov.: 31 AF XY: 0.634 AC XY: 46952 AN XY: 74048

Gnomad4 AFR AF: 0.491

Gnomad4 AMR AF: 0.570

Gnomad4 ASJ AF: 0.761

Gnomad4 EAS AF: 0.803

Gnomad4 SAS AF: 0.607

Gnomad4 FIN AF: 0.709

Gnomad4 NFE AF: 0.709

Gnomad4 OTH AF: 0.652

Alfa AF: 0.697 Hom.: 71641

Bravo AF: 0.621

TwinsUK AF: 0.717 AC: 2658

ALSPAC AF: 0.715 AC: 2757

ESP6500AA AF: 0.504 AC: 2216

ESP6500EA AF: 0.712 AC: 6121

ExAC AF: 0.659 AC: 78696

Asia WGS AF: 0.730 AC: 2535 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	17
DANN	Uncertain	0.98
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.57	T;T;T;T
MetaRNN	Benign	0.0000016	T;T;T;T
MetaSVM	Benign	-0.98	T
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.097	T;T;T;T
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		0.74	P;D;P;P
Vest4		0.46
ClinPred		0.013	T
GERP RS		3.0
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2246901; hg19: chr3-195489009; COSMIC: COSV57763148; COSMIC: COSV57763148;