4-76754772-G-A

Position:

• chr4-76754772-G-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.4289G>A​(p.Arg1430Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0468 in 1,614,086 control chromosomes in the GnomAD database, including 2,287 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (193 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2094 hom.)
• Consequence: SHROOM3 NM_020859.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.799

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=0.0017259121).
• BP6: Variant 4-76754772-G-A is Benign according to our data. Variant chr4-76754772-G-A is described in ClinVar as [Benign]. Clinvar id is 403442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHROOM3	NM_020859.4	c.4289G>A	p.Arg1430Gln	missense_variant	7/11	ENST00000296043.7	NP_065910.3
SHROOM3-AS1	XR_938903.3	n.1061+3277C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHROOM3	ENST00000296043.7	c.4289G>A	p.Arg1430Gln	missense_variant	7/11	1	NM_020859.4	ENSP00000296043	P1
SHROOM3-AS1	ENST00000666924.1	n.356-11872C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0366 AC: 5571 AN: 152142 Hom.: 188 Cov.: 32

Gnomad AFR AF: 0.00985

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0996

Gnomad ASJ AF: 0.0562

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0546

Gnomad FIN AF: 0.00801

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0435

Gnomad OTH AF: 0.0473

GnomAD3 exomes AF: 0.0498 AC: 12506 AN: 251020 Hom.: 512 AF XY: 0.0486 AC XY: 6596 AN XY: 135684

Gnomad AFR exome AF: 0.0100

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.0543

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0586

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.0435

Gnomad OTH exome AF: 0.0519

GnomAD4 exome AF: 0.0479 AC: 69968 AN: 1461826 Hom.: 2094 Cov.: 74 AF XY: 0.0478 AC XY: 34752 AN XY: 727212

Gnomad4 AFR exome AF: 0.00797

Gnomad4 AMR exome AF: 0.124

Gnomad4 ASJ exome AF: 0.0572

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0586

Gnomad4 FIN exome AF: 0.0103

Gnomad4 NFE exome AF: 0.0485

Gnomad4 OTH exome AF: 0.0469

GnomAD4 genome AF: 0.0367 AC: 5583 AN: 152260 Hom.: 193 Cov.: 32 AF XY: 0.0374 AC XY: 2787 AN XY: 74452

Gnomad4 AFR AF: 0.00982

Gnomad4 AMR AF: 0.100

Gnomad4 ASJ AF: 0.0562

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.0551

Gnomad4 FIN AF: 0.00801

Gnomad4 NFE AF: 0.0435

Gnomad4 OTH AF: 0.0468

Alfa AF: 0.0414 Hom.: 237

Bravo AF: 0.0424

TwinsUK AF: 0.0518 AC: 192

ALSPAC AF: 0.0428 AC: 165

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.0449 AC: 386

ExAC AF: 0.0451 AC: 5472

Asia WGS AF: 0.0260 AC: 93 AN: 3478

EpiCase AF: 0.0493

EpiControl AF: 0.0503

ClinVar

Significance: Benign

Submissions summary: Benign:3

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: Frequency -

SHROOM3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 06, 2020

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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.2
DANN	Benign	0.84
DEOGEN2	Benign	0.062	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.62	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.51	N;.
REVEL	Benign	0.015
Sift	Benign	0.37	T;.
Sift4G	Benign	0.60	T;.
Polyphen		0.0040	B;.
Vest4		0.037
MPC		0.36
ClinPred		0.00088	T
GERP RS		1.9
Varity_R		0.023
gMVP		0.10

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: rs61741104; hg19: chr4-77675925;