3-195784460-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018406.7(MUC4):​c.7120T>C​(p.Ser2374Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.74 in 640,450 control chromosomes in the GnomAD database, including 179,779 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (9807 hom., cov: 0)
  • Exomes 𝑓: 0.75 (169972 hom.)
• Consequence: MUC4 NM_018406.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.715618E-5).
• BP6: Variant 3-195784460-A-G is Benign according to our data. Variant chr3-195784460-A-G is described in ClinVar as [Benign]. Clinvar id is 403122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC4	NM_018406.7	c.7120T>C	p.Ser2374Pro	missense_variant	Exon 2 of 25	ENST00000463781.8	NP_060876.5
MUC4	NM_004532.6	c.83-6005T>C		intron_variant	Intron 1 of 23		NP_004523.3
MUC4	NM_138297.5	c.83-10155T>C		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>C	p.Ser2374Pro	missense_variant	Exon 2 of 25	5	NM_018406.7	ENSP00000417498.3

Frequencies

GnomAD3 genomes AF: 0.610 AC: 39093 AN: 64120 Hom.: 9793 Cov.: 0

Gnomad AFR AF: 0.724

Gnomad AMI AF: 0.580

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.544

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.546

Gnomad MID AF: 0.619

Gnomad NFE AF: 0.574

Gnomad OTH AF: 0.601

GnomAD4 exome AF: 0.754 AC: 434702 AN: 576276 Hom.: 169972 Cov.: 295 AF XY: 0.745 AC XY: 208112 AN XY: 279334

African (AFR) AF: 0.821 AC: 7938 AN: 9666

American (AMR) AF: 0.394 AC: 3351 AN: 8512

Ashkenazi Jewish (ASJ) AF: 0.793 AC: 5165 AN: 6514

East Asian (EAS) AF: 0.614 AC: 2810 AN: 4580

South Asian (SAS) AF: 0.505 AC: 14292 AN: 28274

European-Finnish (FIN) AF: 0.517 AC: 4800 AN: 9280

Middle Eastern (MID) AF: 0.780 AC: 1801 AN: 2310

European-Non Finnish (NFE) AF: 0.779 AC: 379109 AN: 486402

Other (OTH) AF: 0.744 AC: 15436 AN: 20738

GnomAD4 genome AF: 0.610 AC: 39131 AN: 64174 Hom.: 9807 Cov.: 0 AF XY: 0.606 AC XY: 18789 AN XY: 31016

African (AFR) AF: 0.724 AC: 13378 AN: 18468

American (AMR) AF: 0.542 AC: 3264 AN: 6018

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 708 AN: 1242

East Asian (EAS) AF: 0.543 AC: 914 AN: 1684

South Asian (SAS) AF: 0.502 AC: 1090 AN: 2170

European-Finnish (FIN) AF: 0.546 AC: 2118 AN: 3876

Middle Eastern (MID) AF: 0.628 AC: 103 AN: 164

European-Non Finnish (NFE) AF: 0.574 AC: 16813 AN: 29306

Other (OTH) AF: 0.603 AC: 540 AN: 896

Alfa AF: 0.986 Hom.: 6564

ExAC AF: 0.786 AC: 48549

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.6
DANN	Benign	0.69
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.45	T;T
MetaRNN	Benign	0.000087	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.63	N;N
REVEL	Benign	0.0030
Sift	Benign	0.13	T;T
Sift4G	Benign	0.097	T;T
Vest4		0.051
ClinPred		0.039	T
gMVP		0.0028
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV62127672;