rs6909677

Variant names:

• chr6-148540580-G-A
• rs6909677
• NM_015278.5:c.2209+24G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015278.5(SASH1):​c.2209+24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,561,418 control chromosomes in the GnomAD database, including 15,213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.14 (1584 hom., cov: 31)
  • Exomes 𝑓: 0.14 (13629 hom.)
• Consequence: SASH1 NM_015278.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.678
• Publications: 7 publications found

Genes affected

SASH1 (HGNC:19182): (SAM and SH3 domain containing 1) This gene encodes a scaffold protein involved in the TLR4 signaling pathway that may stimulate cytokine production and endothelial cell migration in response to invading pathogens. The encoded protein has also been described as a potential tumor suppressor that may negatively regulate proliferation, apoptosis, and invasion of cancer cells, and reduced expression of this gene has been observed in multiple human cancers. Mutations in this gene may be associated with abnormal skin pigmentation in human patients. [provided by RefSeq, Oct 2016]

SASH1 Gene-Disease associations (from GenCC):

• dyschromatosis universalis hereditaria 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• familial generalized lentiginosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-148540580-G-A is Benign according to our data. Variant chr6-148540580-G-A is described in ClinVar as Benign. ClinVar VariationId is 1285745.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SASH1	NM_015278.5	c.2209+24G>A		intron_variant	Intron 17 of 19	ENST00000367467.8	NP_056093.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SASH1	ENST00000367467.8	c.2209+24G>A		intron_variant	Intron 17 of 19	1	NM_015278.5	ENSP00000356437.3

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21458 AN: 151970 Hom.: 1584 Cov.: 31

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.126

GnomAD2 exomes AF: 0.139 AC: 33151 AN: 238624 AF XY: 0.140

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.115

Gnomad FIN exome AF: 0.202

Gnomad NFE exome AF: 0.148

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.137 AC: 192561 AN: 1409330 Hom.: 13629 Cov.: 22 AF XY: 0.137 AC XY: 96134 AN XY: 703658

African (AFR) AF: 0.124 AC: 4010 AN: 32282

American (AMR) AF: 0.111 AC: 4867 AN: 43852

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 3334 AN: 25766

East Asian (EAS) AF: 0.0813 AC: 3174 AN: 39052

South Asian (SAS) AF: 0.119 AC: 10038 AN: 84332

European-Finnish (FIN) AF: 0.201 AC: 10589 AN: 52724

Middle Eastern (MID) AF: 0.130 AC: 738 AN: 5684

European-Non Finnish (NFE) AF: 0.139 AC: 148072 AN: 1067066

Other (OTH) AF: 0.132 AC: 7739 AN: 58572

GnomAD4 genome AF: 0.141 AC: 21459 AN: 152088 Hom.: 1584 Cov.: 31 AF XY: 0.144 AC XY: 10667 AN XY: 74314

African (AFR) AF: 0.123 AC: 5100 AN: 41490

American (AMR) AF: 0.137 AC: 2101 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 453 AN: 3468

East Asian (EAS) AF: 0.107 AC: 552 AN: 5154

South Asian (SAS) AF: 0.112 AC: 539 AN: 4814

European-Finnish (FIN) AF: 0.209 AC: 2212 AN: 10568

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 9961 AN: 67992

Other (OTH) AF: 0.125 AC: 264 AN: 2112

Alfa AF: 0.142 Hom.: 5524

Bravo AF: 0.132

Asia WGS AF: 0.111 AC: 385 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.4
DANN	Benign	0.83
PhyloP100		0.68
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6909677; hg19: chr6-148861716; COSMIC: COSV66561792;