chr6-148350012-A-C

Variant names:

• chr6-148350012-A-C
• rs11155563
• NM_015278.5:c.156+6789A>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.156+6789A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 151,722 control chromosomes in the GnomAD database, including 3,906 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 0.21 (3906 hom., cov: 31)
• Consequence: SASH1 NM_015278.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.99
• Publications: 2 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=-1.04).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SASH1	NM_015278.5	c.156+6789A>C		intron_variant	Intron 1 of 19	ENST00000367467.8	NP_056093.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SASH1	ENST00000367467.8	c.156+6789A>C		intron_variant	Intron 1 of 19	1	NM_015278.5	ENSP00000356437.3
SASH1	ENST00000367469.5	n.75-40122A>C		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32441 AN: 151604 Hom.: 3910 Cov.: 31

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.311

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.224

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

GnomAD4 genome AF: 0.214 AC: 32445 AN: 151722 Hom.: 3906 Cov.: 31 AF XY: 0.209 AC XY: 15520 AN XY: 74114

African (AFR) AF: 0.120 AC: 4977 AN: 41392

American (AMR) AF: 0.171 AC: 2608 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 792 AN: 3464

East Asian (EAS) AF: 0.129 AC: 658 AN: 5102

South Asian (SAS) AF: 0.144 AC: 691 AN: 4810

European-Finnish (FIN) AF: 0.250 AC: 2630 AN: 10518

Middle Eastern (MID) AF: 0.310 AC: 90 AN: 290

European-Non Finnish (NFE) AF: 0.283 AC: 19203 AN: 67878

Other (OTH) AF: 0.224 AC: 472 AN: 2106

Alfa AF: 0.232 Hom.: 562

Bravo AF: 0.207

Asia WGS AF: 0.132 AC: 459 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.95
DANN	Benign	0.11
PhyloP100		-3.0
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: rs11155563; hg19: chr6-148671148; COSMIC: COSV66560048;