4-76710272-T-A

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.440T>A(p.Leu147His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,613,726 control chromosomes in the GnomAD database, including 20,924 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 0.16 (2197 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18727 hom.)
• Consequence: SHROOM3 NM_020859.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.230

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=0.002124101).
• BP6: Variant 4-76710272-T-A is Benign according to our data. Variant chr4-76710272-T-A is described in ClinVar as [Benign]. Clinvar id is 1238813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHROOM3	NM_020859.4	c.440T>A	p.Leu147His	missense_variant	3/11	ENST00000296043.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHROOM3	ENST00000296043.7	c.440T>A	p.Leu147His	missense_variant	3/11	1	NM_020859.4	P1
SHROOM3-AS1	ENST00000666924.1	n.571A>T		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24605 AN: 151912 Hom.: 2192 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.152

GnomAD3 exomes AF: 0.180 AC: 45234 AN: 251104 Hom.: 4808 AF XY: 0.182 AC XY: 24768 AN XY: 135720

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.201

Gnomad ASJ exome AF: 0.110

Gnomad EAS exome AF: 0.345

Gnomad SAS exome AF: 0.290

Gnomad FIN exome AF: 0.135

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.151 AC: 221265 AN: 1461696 Hom.: 18727 Cov.: 32 AF XY: 0.155 AC XY: 112592 AN XY: 727170

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.200

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.274

Gnomad4 SAS exome AF: 0.288

Gnomad4 FIN exome AF: 0.139

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.159

GnomAD4 genome AF: 0.162 AC: 24631 AN: 152030 Hom.: 2197 Cov.: 32 AF XY: 0.165 AC XY: 12298 AN XY: 74334

Gnomad4 AFR AF: 0.181

Gnomad4 AMR AF: 0.183

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.331

Gnomad4 SAS AF: 0.296

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.156

Alfa AF: 0.137 Hom.: 466

Bravo AF: 0.165

TwinsUK AF: 0.131 AC: 487

ALSPAC AF: 0.135 AC: 521

ESP6500AA AF: 0.172 AC: 760

ESP6500EA AF: 0.132 AC: 1131

ExAC AF: 0.180 AC: 21805

Asia WGS AF: 0.321 AC: 1115 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SHROOM3-related disorder Benign:1

Benign, criteria provided, single submitter

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

This variant is associated with the following publications: (PMID: 16574953) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.20	T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.49	T;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	0.30	P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.3	N;.
REVEL	Benign	0.077
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0070	D;.
Polyphen		1.0	D;.
Vest4		0.12
MPC		0.93
ClinPred		0.026	T
GERP RS		3.8
Varity_R		0.19
gMVP		0.41

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: rs3821979; hg19: chr4-77631425; COSMIC: COSV56037218;