chr6-148504812-G-A

Variant names:

• chr6-148504812-G-A
• rs6570858
• NM_015278.5:c.730-9512G>A

Variant summary

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

The NM_015278.5(SASH1):​c.730-9512G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 152,032 control chromosomes in the GnomAD database, including 5,333 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 0.26 (5333 hom., cov: 31)
• Consequence: SASH1 NM_015278.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.694
• Publications: 9 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SASH1	NM_015278.5	c.730-9512G>A		intron_variant	Intron 8 of 19	ENST00000367467.8	NP_056093.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SASH1	ENST00000367467.8	c.730-9512G>A		intron_variant	Intron 8 of 19	1	NM_015278.5	ENSP00000356437.3
SASH1	ENST00000637469.1	n.*50-9512G>A		intron_variant	Intron 3 of 4	4		ENSP00000490499.1

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38953 AN: 151914 Hom.: 5336 Cov.: 31

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.265

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

GnomAD4 genome AF: 0.256 AC: 38958 AN: 152032 Hom.: 5333 Cov.: 31 AF XY: 0.257 AC XY: 19090 AN XY: 74300

African (AFR) AF: 0.165 AC: 6857 AN: 41480

American (AMR) AF: 0.256 AC: 3908 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 940 AN: 3468

East Asian (EAS) AF: 0.146 AC: 755 AN: 5166

South Asian (SAS) AF: 0.268 AC: 1289 AN: 4804

European-Finnish (FIN) AF: 0.300 AC: 3162 AN: 10554

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.309 AC: 21000 AN: 67958

Other (OTH) AF: 0.263 AC: 556 AN: 2116

Alfa AF: 0.292 Hom.: 4367

Bravo AF: 0.248

Asia WGS AF: 0.180 AC: 624 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.10
DANN	Benign	0.57
PhyloP100		-0.69
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: rs6570858; hg19: chr6-148825948;