chr5-132825356-T-A

Variant names:

• chr5-132825356-T-A
• rs369587593
• NM_001172700.2:c.785A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001172700.2(SHROOM1):​c.785A>T​(p.His262Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000559 in 1,448,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: SHROOM1 NM_001172700.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.56

Genes affected

SHROOM1 (HGNC:24084): (shroom family member 1) SHROOM family members play diverse roles in the development of the nervous system and other tissues (Hagens et al., 2006 [PubMed 16615870]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06275302).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHROOM1	NM_001172700.2	c.785A>T	p.His262Leu	missense_variant	Exon 4 of 10	ENST00000378679.8	NP_001166171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHROOM1	ENST00000378679.8	c.785A>T	p.His262Leu	missense_variant	Exon 4 of 10	1	NM_001172700.2	ENSP00000367950.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000214 AC: 5 AN: 233748 AF XY: 0.00000782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000460

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000559 AC: 81 AN: 1448564 Hom.: 0 Cov.: 32 AF XY: 0.0000527 AC XY: 38 AN XY: 720980

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 85826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000711 AC: 79 AN: 1111128

Other (OTH) AF: 0.0000332 AC: 2 AN: 60210

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.785A>T (p.H262L) alteration is located in exon 4 (coding exon 1) of the SHROOM1 gene. This alteration results from a A to T substitution at nucleotide position 785, causing the histidine (H) at amino acid position 262 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.76
DANN	Benign	0.77
DEOGEN2	Benign	0.030	T;T;.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.37	.;T;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.063	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.20	N;N;N;.;.
PhyloP100		-3.6
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.2	N;.;N;D;D
REVEL	Benign	0.021
Sift	Benign	0.042	D;.;D;D;T
Sift4G	Benign	0.46	T;T;T;T;T
Polyphen		0.072	B;B;B;.;.
Vest4		0.10
MVP		0.26
MPC		0.016
ClinPred		0.052	T
GERP RS		-9.4
Varity_R		0.093
gMVP		0.34
Mutation Taster		=99/1	polymorphism

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

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Other links and lift over

dbSNP: rs369587593; hg19: chr5-132161048;