6-148486077-T-C

Variant names:

• chr6-148486077-T-C
• rs11961740
• NM_015278.5:c.628-1537T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015278.5(SASH1):​c.628-1537T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 152,176 control chromosomes in the GnomAD database, including 2,497 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2497 hom., cov: 33)
• Consequence: SASH1 NM_015278.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.574
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SASH1	NM_015278.5	c.628-1537T>C		intron_variant	Intron 7 of 19	ENST00000367467.8	NP_056093.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SASH1	ENST00000367467.8	c.628-1537T>C		intron_variant	Intron 7 of 19	1	NM_015278.5	ENSP00000356437.3
SASH1	ENST00000637469.1	n.71-1537T>C		intron_variant	Intron 2 of 4	4		ENSP00000490499.1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25436 AN: 152058 Hom.: 2490 Cov.: 33

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.161

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.167 AC: 25451 AN: 152176 Hom.: 2497 Cov.: 33 AF XY: 0.167 AC XY: 12398 AN XY: 74400

African (AFR) AF: 0.280 AC: 11623 AN: 41502

American (AMR) AF: 0.104 AC: 1586 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 495 AN: 3470

East Asian (EAS) AF: 0.129 AC: 666 AN: 5178

South Asian (SAS) AF: 0.212 AC: 1023 AN: 4816

European-Finnish (FIN) AF: 0.134 AC: 1424 AN: 10588

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8084 AN: 68022

Other (OTH) AF: 0.161 AC: 341 AN: 2114

Alfa AF: 0.125 Hom.: 1842

Bravo AF: 0.168

Asia WGS AF: 0.191 AC: 664 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.4
DANN	Benign	0.46
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11961740; hg19: chr6-148807213; COSMIC: COSV66565241;