10-111011593-ATT-AT

Variant names:

• chr10-111011593-AT-A
• rs371544139
• NM_007373.4:c.1541-7delT

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_007373.4(SHOC2):​c.1541-7delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00728 in 1,533,536 control chromosomes in the GnomAD database, including 63 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (54 hom.)
• Consequence: SHOC2 NM_007373.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.46

Genes affected

SHOC2 (HGNC:15454): (SHOC2 leucine rich repeat scaffold protein) This gene encodes a protein that consists almost entirely of leucine-rich repeats, a domain implicated in protein-protein interactions. The protein may function as a scaffold linking RAS to downstream signal transducers in the RAS/ERK MAP kinase signaling cascade. Mutations in this gene have been associated with Noonan-like syndrome with loose anagen hair. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 10-111011593-AT-A is Benign according to our data. Variant chr10-111011593-AT-A is described in ClinVar as [Likely_benign]. Clinvar id is 928786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-111011593-AT-A is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 912 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHOC2	NM_007373.4	c.1541-7delT		splice_region_variant, intron_variant	Intron 8 of 8	ENST00000369452.9	NP_031399.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHOC2	ENST00000369452.9	c.1541-16delT		intron_variant	Intron 8 of 8	1	NM_007373.4	ENSP00000358464.5

Frequencies

GnomAD3 genomes AF: 0.00604 AC: 911 AN: 150756 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00503

Gnomad ASJ AF: 0.000869

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0290

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00705

Gnomad OTH AF: 0.00530

GnomAD3 exomes AF: 0.00704 AC: 1575 AN: 223736 Hom.: 12 AF XY: 0.00700 AC XY: 849 AN XY: 121300

Gnomad AFR exome AF: 0.00145

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.000662

Gnomad EAS exome AF: 0.000356

Gnomad SAS exome AF: 0.000221

Gnomad FIN exome AF: 0.0337

Gnomad NFE exome AF: 0.00836

Gnomad OTH exome AF: 0.00714

GnomAD4 exome AF: 0.00741 AC: 10251 AN: 1382662 Hom.: 54 Cov.: 28 AF XY: 0.00705 AC XY: 4872 AN XY: 690804

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.00194

Gnomad4 ASJ exome AF: 0.000556

Gnomad4 EAS exome AF: 0.0000517

Gnomad4 SAS exome AF: 0.000190

Gnomad4 FIN exome AF: 0.0278

Gnomad4 NFE exome AF: 0.00794

Gnomad4 OTH exome AF: 0.00652

GnomAD4 genome AF: 0.00604 AC: 912 AN: 150874 Hom.: 9 Cov.: 32 AF XY: 0.00695 AC XY: 512 AN XY: 73694

Gnomad4 AFR AF: 0.00107

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.000869

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0290

Gnomad4 NFE AF: 0.00706

Gnomad4 OTH AF: 0.00525

Alfa AF: 0.00354 Hom.: 0

Bravo AF: 0.00446

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 01, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SHOC2 c.1541-7delT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.007 in 223736 control chromosomes in the gnomAD database, including 12 homozygotes. The observed variant frequency is approximately 282 fold of the estimated maximal expected allele frequency for a pathogenic variant in SHOC2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1541-7delT in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Jan 09, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SHOC2: BP4, BS1, BS2 -

Noonan syndrome-like disorder with loose anagen hair 1 Benign:1

Nov 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SHOC2-related disorder Benign:1

May 08, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Noonan syndrome and Noonan-related syndrome Benign:1

May 07, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs371544139; hg19: chr10-112771351;