rs61999292

chr4-76739146-T-G

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.973T>G(p.Ser325Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0783 in 1,614,028 control chromosomes in the GnomAD database, including 5,582 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (371 hom., cov: 33)
  • Exomes 𝑓: 0.080 (5211 hom.)
• Consequence: SHROOM3 NM_020859.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.68

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=0.0018060207).
• BP6: Variant 4-76739146-T-G is Benign according to our data. Variant chr4-76739146-T-G is described in ClinVar as [Benign]. Clinvar id is 403438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-76739146-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHROOM3	NM_020859.4	c.973T>G	p.Ser325Ala	missense_variant	5/11	ENST00000296043.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHROOM3	ENST00000296043.7	c.973T>G	p.Ser325Ala	missense_variant	5/11	1	NM_020859.4	P1
SHROOM3-AS1	ENST00000666924.1	n.448+3662A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0584 AC: 8877 AN: 152120 Hom.: 372 Cov.: 33

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0623

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0413

Gnomad FIN AF: 0.0638

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0845

Gnomad OTH AF: 0.0789

GnomAD3 exomes AF: 0.0643 AC: 16146 AN: 251086 Hom.: 677 AF XY: 0.0658 AC XY: 8928 AN XY: 135710

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.0453

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.0407

Gnomad FIN exome AF: 0.0641

Gnomad NFE exome AF: 0.0887

Gnomad OTH exome AF: 0.0800

GnomAD4 exome AF: 0.0803 AC: 117433 AN: 1461790 Hom.: 5211 Cov.: 76 AF XY: 0.0795 AC XY: 57790 AN XY: 727180

Gnomad4 AFR exome AF: 0.0151

Gnomad4 AMR exome AF: 0.0486

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0425

Gnomad4 FIN exome AF: 0.0624

Gnomad4 NFE exome AF: 0.0893

Gnomad4 OTH exome AF: 0.0788

GnomAD4 genome AF: 0.0582 AC: 8866 AN: 152238 Hom.: 371 Cov.: 33 AF XY: 0.0566 AC XY: 4213 AN XY: 74452

Gnomad4 AFR AF: 0.0152

Gnomad4 AMR AF: 0.0622

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0407

Gnomad4 FIN AF: 0.0638

Gnomad4 NFE AF: 0.0845

Gnomad4 OTH AF: 0.0777

Alfa AF: 0.0816 Hom.: 832

Bravo AF: 0.0587

TwinsUK AF: 0.0866 AC: 321

ALSPAC AF: 0.0838 AC: 323

ESP6500AA AF: 0.0166 AC: 73

ESP6500EA AF: 0.0929 AC: 799

ExAC AF: 0.0629 AC: 7640

Asia WGS AF: 0.0190 AC: 66 AN: 3478

EpiCase AF: 0.0985

EpiControl AF: 0.103

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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: MAF -

SHROOM3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 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	0.089
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.064	T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.69	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	0.77	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N;.
REVEL	Benign	0.084
Sift	Benign	0.048	D;.
Sift4G	Benign	0.18	T;.
Polyphen		0.95	P;.
Vest4		0.090
MPC		0.35
ClinPred		0.023	T
GERP RS		3.8
Varity_R		0.062
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: rs61999292; hg19: chr4-77660299; COSMIC: COSV56027088; COSMIC: COSV56027088;