4-76739009-G-C

Position:

• chr4-76739009-G-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
SHROOM3	NM_020859.4	c.836G>C	p.Gly279Ala	missense_variant	5/11	ENST00000296043.7	NP_065910.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHROOM3	ENST00000296043.7	c.836G>C	p.Gly279Ala	missense_variant	5/11	1	NM_020859.4	ENSP00000296043	P1
SHROOM3-AS1	ENST00000666924.1	n.448+3799C>G		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.718 AC: 180327 AN: 251200 Hom.: 65126 AF XY: 0.722 AC XY: 98014 AN XY: 135776

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 SAS exome AF: 0.734

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

Gnomad4 AFR exome AF: 0.626

Gnomad4 AMR exome AF: 0.710

Gnomad4 ASJ exome AF: 0.749

Gnomad4 EAS exome AF: 0.512

Gnomad4 SAS exome AF: 0.733

Gnomad4 FIN exome AF: 0.698

Gnomad4 NFE exome AF: 0.756

Gnomad4 OTH exome AF: 0.730

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

Gnomad4 AFR AF: 0.631

Gnomad4 AMR AF: 0.722

Gnomad4 ASJ AF: 0.747

Gnomad4 EAS AF: 0.578

Gnomad4 SAS AF: 0.724

Gnomad4 FIN AF: 0.707

Gnomad4 NFE AF: 0.750

Gnomad4 OTH AF: 0.707

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 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 -

SHROOM3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2019

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;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.81	N;.
REVEL	Benign	0.18
Sift	Benign	0.70	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0020	B;.
Vest4		0.010
MPC		0.34
ClinPred		0.010	T
GERP RS		-0.95
Varity_R		0.029
gMVP		0.076

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: rs344140; hg19: chr4-77660162; COSMIC: COSV56024450; COSMIC: COSV56024450;