11-1250004-C-T

Position:

• chr11-1250004-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002458.3(MUC5B):​c.13124C>T​(p.Ala4375Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0249 in 1,600,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.026 (0 hom.)
• Consequence: MUC5B NM_002458.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -7.65

Genes affected

MUC5B (HGNC:7516): (mucin 5B, oligomeric mucus/gel-forming) This gene encodes a member of the mucin family of proteins, which are highly glycosylated macromolecular components of mucus secretions. This family member is the major gel-forming mucin in mucus. It is a major contributor to the lubricating and viscoelastic properties of whole saliva, normal lung mucus and cervical mucus. This gene has been found to be up-regulated in some human diseases, including sinus mucosa of chronic rhinosinusitis (CRS), CRS with nasal polyposis, chronic obstructive pulmonary disease (COPD) and H. pylori-associated gastric disease, and it may be involved in the pathogenesis of these diseases. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036114454).
• BP6: Variant 11-1250004-C-T is Benign according to our data. Variant chr11-1250004-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 403191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0145 (2169/149756) while in subpopulation NFE AF= 0.0214 (1425/66554). AF 95% confidence interval is 0.0205. There are 0 homozygotes in gnomad4. There are 1053 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2169 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUC5B	NM_002458.3	c.13124C>T	p.Ala4375Val	missense_variant	31/49	ENST00000529681.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUC5B	ENST00000529681.5	c.13124C>T	p.Ala4375Val	missense_variant	31/49	5	NM_002458.3	P1

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2167 AN: 149632 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00402

Gnomad ASJ AF: 0.0165

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00564

Gnomad FIN AF: 0.0428

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0116

GnomAD3 exomes AF: 0.0188 AC: 4618 AN: 245546 Hom.: 0 AF XY: 0.0184 AC XY: 2455 AN XY: 133186

Gnomad AFR exome AF: 0.00382

Gnomad AMR exome AF: 0.00285

Gnomad ASJ exome AF: 0.0198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00537

Gnomad FIN exome AF: 0.0622

Gnomad NFE exome AF: 0.0243

Gnomad OTH exome AF: 0.0185

GnomAD4 exome AF: 0.0259 AC: 37610 AN: 1450250 Hom.: 0 Cov.: 120 AF XY: 0.0253 AC XY: 18246 AN XY: 721362

Gnomad4 AFR exome AF: 0.00308

Gnomad4 AMR exome AF: 0.00419

Gnomad4 ASJ exome AF: 0.0246

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00708

Gnomad4 FIN exome AF: 0.0612

Gnomad4 NFE exome AF: 0.0285

Gnomad4 OTH exome AF: 0.0229

GnomAD4 genome AF: 0.0145 AC: 2169 AN: 149756 Hom.: 0 Cov.: 32 AF XY: 0.0144 AC XY: 1053 AN XY: 73106

Gnomad4 AFR AF: 0.00344

Gnomad4 AMR AF: 0.00401

Gnomad4 ASJ AF: 0.0165

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00564

Gnomad4 FIN AF: 0.0428

Gnomad4 NFE AF: 0.0214

Gnomad4 OTH AF: 0.0115

Alfa AF: 0.0239 Hom.: 0

ESP6500AA AF: 0.00633 AC: 27

ESP6500EA AF: 0.0245 AC: 207

ExAC AF: 0.0264 AC: 3202

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.17
DANN	Benign	0.46
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00084	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.032
Sift	Uncertain	0.021	D
Vest4		0.014
ClinPred		0.0063	T
GERP RS		-3.4
Varity_R		0.044
gMVP		0.27

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: rs201748966; hg19: chr11-1271234; COSMIC: COSV71594265; COSMIC: COSV71594265;