NM_015278.5:c.387-2522C>T

Variant names:

• chr6-148466023-C-T
• rs12527089
• NM_015278.5:c.387-2522C>T

Variant summary

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

The NM_015278.5(SASH1):​c.387-2522C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0463 in 152,170 control chromosomes in the GnomAD database, including 248 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 0.046 (248 hom., cov: 32)
• Consequence: SASH1 NM_015278.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.974
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015278.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SASH1	NM_015278.5	MANE Select	c.387-2522C>T		intron	N/A	NP_056093.3
	SASH1	NM_001346505.2		c.252-2522C>T		intron	N/A	NP_001333434.1
	SASH1	NM_001346506.2		c.15-2522C>T		intron	N/A	NP_001333435.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SASH1	ENST00000367467.8	TSL:1 MANE Select	c.387-2522C>T		intron	N/A	ENSP00000356437.3
	SASH1	ENST00000470750.1	TSL:3	n.51-2522C>T		intron	N/A
	SASH1	ENST00000637469.1	TSL:4	n.30-2522C>T		intron	N/A	ENSP00000490499.1

Frequencies

GnomAD3 genomes AF: 0.0464 AC: 7052 AN: 152052 Hom.: 249 Cov.: 32

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.0152

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.0651

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0484

Gnomad OTH AF: 0.0392

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

GnomAD4 genome AF: 0.0463 AC: 7052 AN: 152170 Hom.: 248 Cov.: 32 AF XY: 0.0507 AC XY: 3774 AN XY: 74374

African (AFR) AF: 0.0147 AC: 609 AN: 41512

American (AMR) AF: 0.0999 AC: 1527 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3472

East Asian (EAS) AF: 0.0153 AC: 79 AN: 5180

South Asian (SAS) AF: 0.137 AC: 660 AN: 4826

European-Finnish (FIN) AF: 0.0651 AC: 687 AN: 10556

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0484 AC: 3290 AN: 68020

Other (OTH) AF: 0.0388 AC: 82 AN: 2112

Alfa AF: 0.0488 Hom.: 637

Bravo AF: 0.0444

Asia WGS AF: 0.114 AC: 396 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.2
DANN	Benign	0.75
PhyloP100		0.97
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: rs12527089; hg19: chr6-148787159;