4-76710205-G-A

Variant names:

• chr4-76710205-G-A
• rs548266561
• NM_020859.4:c.373G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_020859.4(SHROOM3):​c.373G>A​(p.Val125Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: SHROOM3 NM_020859.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.631

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018149436).
• BP6: Variant 4-76710205-G-A is Benign according to our data. Variant chr4-76710205-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3441627.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM3	NM_020859.4	c.373G>A	p.Val125Ile	missense_variant	Exon 3 of 11	ENST00000296043.7	NP_065910.3
SHROOM3-AS1	NR_187404.1	n.1234C>T		non_coding_transcript_exon_variant	Exon 4 of 4
SHROOM3-AS1	NR_187405.1	n.690C>T		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHROOM3	ENST00000296043.7	c.373G>A	p.Val125Ile	missense_variant	Exon 3 of 11	1	NM_020859.4	ENSP00000296043.6

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000143 AC: 36 AN: 250926 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135648

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000114 AC: 167 AN: 1461856 Hom.: 0 Cov.: 30 AF XY: 0.000139 AC XY: 101 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74424

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000676 Hom.: 0

Bravo AF: 0.0000491

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000181 AC: 22

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 07, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.75
DANN	Benign	0.69
DEOGEN2	Benign	0.014	T;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.26	T;T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	N;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.21	N;.
REVEL	Benign	0.0030
Sift	Benign	0.32	T;.
Sift4G	Benign	0.11	T;.
Polyphen		0.0010	B;.
Vest4		0.025
MutPred		0.30		Gain of catalytic residue at P127 (P = 0.0305);.;
MVP		0.17
MPC		0.25
ClinPred		0.021	T
GERP RS		-8.6
Varity_R		0.012
gMVP		0.071

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs548266561; hg19: chr4-77631358;