4-76739578-C-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.1405C>G(p.Pro469Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.58 in 1,613,930 control chromosomes in the GnomAD database, including 277,640 homozygotes. In-silico tool predicts 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 0.54 (22639 hom., cov: 32)
  • Exomes 𝑓: 0.58 (255001 hom.)
• Consequence: SHROOM3 NM_020859.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.33

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=1.1504435E-5).
• BP6: Variant 4-76739578-C-G is Benign according to our data. Variant chr4-76739578-C-G is described in ClinVar as [Benign]. Clinvar id is 403439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHROOM3	NM_020859.4	c.1405C>G	p.Pro469Ala	missense_variant	5/11	ENST00000296043.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHROOM3	ENST00000296043.7	c.1405C>G	p.Pro469Ala	missense_variant	5/11	1	NM_020859.4	P1
SHROOM3-AS1	ENST00000666924.1	n.448+3230G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.536 AC: 81511 AN: 151956 Hom.: 22615 Cov.: 32

Gnomad AFR AF: 0.432

Gnomad AMI AF: 0.755

Gnomad AMR AF: 0.535

Gnomad ASJ AF: 0.643

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.618

Gnomad NFE AF: 0.613

Gnomad OTH AF: 0.549

GnomAD3 exomes AF: 0.537 AC: 134921 AN: 251374 Hom.: 37685 AF XY: 0.539 AC XY: 73208 AN XY: 135870

Gnomad AFR exome AF: 0.432

Gnomad AMR exome AF: 0.507

Gnomad ASJ exome AF: 0.643

Gnomad EAS exome AF: 0.256

Gnomad SAS exome AF: 0.447

Gnomad FIN exome AF: 0.574

Gnomad NFE exome AF: 0.612

Gnomad OTH exome AF: 0.564

GnomAD4 exome AF: 0.585 AC: 854693 AN: 1461854 Hom.: 255001 Cov.: 78 AF XY: 0.582 AC XY: 423230 AN XY: 727216

Gnomad4 AFR exome AF: 0.423

Gnomad4 AMR exome AF: 0.508

Gnomad4 ASJ exome AF: 0.648

Gnomad4 EAS exome AF: 0.246

Gnomad4 SAS exome AF: 0.448

Gnomad4 FIN exome AF: 0.567

Gnomad4 NFE exome AF: 0.616

Gnomad4 OTH exome AF: 0.566

GnomAD4 genome AF: 0.537 AC: 81589 AN: 152076 Hom.: 22639 Cov.: 32 AF XY: 0.530 AC XY: 39427 AN XY: 74336

Gnomad4 AFR AF: 0.433

Gnomad4 AMR AF: 0.535

Gnomad4 ASJ AF: 0.643

Gnomad4 EAS AF: 0.255

Gnomad4 SAS AF: 0.433

Gnomad4 FIN AF: 0.578

Gnomad4 NFE AF: 0.613

Gnomad4 OTH AF: 0.547

Alfa AF: 0.596 Hom.: 20588

Bravo AF: 0.532

TwinsUK AF: 0.618 AC: 2291

ALSPAC AF: 0.613 AC: 2363

ESP6500AA AF: 0.441 AC: 1943

ESP6500EA AF: 0.614 AC: 5282

ExAC AF: 0.534 AC: 64862

Asia WGS AF: 0.354 AC: 1233 AN: 3478

EpiCase AF: 0.629

EpiControl AF: 0.621

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, 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

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.35	T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.70	T;T
MetaRNN	Benign	0.000012	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	0.0027	P
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Benign	0.12
Sift	Benign	0.049	D;.
Sift4G	Benign	0.27	T;.
Polyphen		0.67	P;.
Vest4		0.12
MPC		0.31
ClinPred		0.034	T
GERP RS		4.6
Varity_R		0.11
gMVP		0.33

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: rs344141; hg19: chr4-77660731; COSMIC: COSV56023464; COSMIC: COSV56023464;