4-76555656-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020859.4(SHROOM3):c.216T>C(p.Ala72=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,614,060 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (40 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (45 hom.)
• Consequence: SHROOM3 NM_020859.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.89

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-76555656-T-C is Benign according to our data. Variant chr4-76555656-T-C is described in ClinVar as [Benign]. Clinvar id is 785098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.89 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.014 (2137/152236) while in subpopulation AFR AF= 0.0489 (2031/41546). AF 95% confidence interval is 0.0471. There are 40 homozygotes in gnomad4. There are 1034 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHROOM3	NM_020859.4	c.216T>C	p.Ala72=	synonymous_variant	2/11	ENST00000296043.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHROOM3	ENST00000296043.7	c.216T>C	p.Ala72=	synonymous_variant	2/11	1	NM_020859.4	P1
SHROOM3	ENST00000466541.1	n.123T>C		non_coding_transcript_exon_variant	2/3	3
SHROOM3	ENST00000469923.5	n.43T>C		non_coding_transcript_exon_variant	1/5	3
SHROOM3	ENST00000497440.5	n.157T>C		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2106 AN: 152118 Hom.: 36 Cov.: 31

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00373 AC: 937 AN: 251448 Hom.: 17 AF XY: 0.00289 AC XY: 393 AN XY: 135900

Gnomad AFR exome AF: 0.0509

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00146 AC: 2139 AN: 1461824 Hom.: 45 Cov.: 32 AF XY: 0.00130 AC XY: 945 AN XY: 727214

Gnomad4 AFR exome AF: 0.0497

Gnomad4 AMR exome AF: 0.00255

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000890

Gnomad4 OTH exome AF: 0.00378

GnomAD4 genome AF: 0.0140 AC: 2137 AN: 152236 Hom.: 40 Cov.: 31 AF XY: 0.0139 AC XY: 1034 AN XY: 74432

Gnomad4 AFR AF: 0.0489

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00696 Hom.: 15

Bravo AF: 0.0157

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

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

Apr 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

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.10
Dann	Benign	0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs75039400; hg19: chr4-77476809;