4-76739009-G-C

Variant names:

• chr4-76739009-G-C
• rs344140
• NM_020859.4:c.836G>C

Variant summary

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

The NM_020859.4(SHROOM3):​c.836G>C​(p.Gly279Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.736 in 1,613,912 control chromosomes in the GnomAD database, including 440,353 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38116 hom., cov: 33)
  • Exomes 𝑓: 0.74 (402237 hom.)
• Consequence: SHROOM3 NM_020859.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.849
• Publications: 36 publications found

Genes affected

SHROOM3 (HGNC:30422): (shroom family member 3) This gene encodes a PDZ-domain-containing protein that belongs to a family of Shroom-related proteins. This protein may be involved in regulating cell shape in certain tissues. A similar protein in mice is required for proper neurulation. [provided by RefSeq, Jan 2011]

SHROOM3-AS1 (HGNC:41265): (SHROOM3 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4019361E-6).
• BP6: Variant 4-76739009-G-C is Benign according to our data. Variant chr4-76739009-G-C is described in ClinVar as Benign. ClinVar VariationId is 403437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM3	NM_020859.4	c.836G>C	p.Gly279Ala	missense_variant	Exon 5 of 11	ENST00000296043.7	NP_065910.3
SHROOM3-AS1	NR_187404.1	n.1044+3799C>G		intron_variant	Intron 3 of 3
SHROOM3-AS1	NR_187405.1	n.500+3799C>G		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHROOM3	ENST00000296043.7	c.836G>C	p.Gly279Ala	missense_variant	Exon 5 of 11	1	NM_020859.4	ENSP00000296043.6

Frequencies

GnomAD3 genomes AF: 0.705 AC: 107154 AN: 152010 Hom.: 38078 Cov.: 33

Gnomad AFR AF: 0.630

Gnomad AMI AF: 0.873

Gnomad AMR AF: 0.722

Gnomad ASJ AF: 0.747

Gnomad EAS AF: 0.578

Gnomad SAS AF: 0.724

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.750

Gnomad OTH AF: 0.706

GnomAD2 exomes AF: 0.718 AC: 180327 AN: 251200 AF XY: 0.722

Gnomad AFR exome AF: 0.628

Gnomad AMR exome AF: 0.710

Gnomad ASJ exome AF: 0.751

Gnomad EAS exome AF: 0.589

Gnomad FIN exome AF: 0.700

Gnomad NFE exome AF: 0.750

Gnomad OTH exome AF: 0.720

GnomAD4 exome AF: 0.740 AC: 1081391 AN: 1461784 Hom.: 402237 Cov.: 79 AF XY: 0.740 AC XY: 538349 AN XY: 727178

African (AFR) AF: 0.626 AC: 20947 AN: 33480

American (AMR) AF: 0.710 AC: 31751 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.749 AC: 19573 AN: 26136

East Asian (EAS) AF: 0.512 AC: 20341 AN: 39694

South Asian (SAS) AF: 0.733 AC: 63200 AN: 86252

European-Finnish (FIN) AF: 0.698 AC: 37262 AN: 53412

Middle Eastern (MID) AF: 0.675 AC: 3895 AN: 5768

European-Non Finnish (NFE) AF: 0.756 AC: 840338 AN: 1111948

Other (OTH) AF: 0.730 AC: 44084 AN: 60394

GnomAD4 genome AF: 0.705 AC: 107255 AN: 152128 Hom.: 38116 Cov.: 33 AF XY: 0.701 AC XY: 52158 AN XY: 74362

African (AFR) AF: 0.631 AC: 26185 AN: 41498

American (AMR) AF: 0.722 AC: 11044 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.747 AC: 2592 AN: 3470

East Asian (EAS) AF: 0.578 AC: 2978 AN: 5156

South Asian (SAS) AF: 0.724 AC: 3490 AN: 4822

European-Finnish (FIN) AF: 0.707 AC: 7479 AN: 10582

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.750 AC: 50972 AN: 67988

Other (OTH) AF: 0.707 AC: 1494 AN: 2114

Alfa AF: 0.742 Hom.: 31579

Bravo AF: 0.706

TwinsUK AF: 0.755 AC: 2799

ALSPAC AF: 0.754 AC: 2905

ESP6500AA AF: 0.629 AC: 2771

ESP6500EA AF: 0.751 AC: 6462

ExAC AF: 0.716 AC: 86891

Asia WGS AF: 0.677 AC: 2353 AN: 3478

EpiCase AF: 0.761

EpiControl AF: 0.751

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

SHROOM3-related disorder Benign:1

Mar 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.53
DANN	Benign	0.10
DEOGEN2	Benign	0.036	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.47	T;T
MetaRNN	Benign	0.0000014	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	L;.
PhyloP100		0.85
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.81	N;.
REVEL	Benign	0.18
Sift	Benign	0.70	T;.
Sift4G	Benign	1.0	T;.
Vest4		0.010
ClinPred		0.010	T
GERP RS		-0.95
Varity_R		0.029
gMVP		0.076
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: rs344140; hg19: chr4-77660162; COSMIC: COSV56024450; COSMIC: COSV56024450;