6-148440320-G-C

Variant names:

• chr6-148440320-G-C
• rs2272998
• NM_015278.5:c.337-38G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015278.5(SASH1):​c.337-38G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,611,128 control chromosomes in the GnomAD database, including 146,131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13727 hom., cov: 30)
  • Exomes 𝑓: 0.42 (132404 hom.)
• Consequence: SASH1 NM_015278.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.88
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 6-148440320-G-C is Benign according to our data. Variant chr6-148440320-G-C is described in ClinVar as Benign. ClinVar VariationId is 1289486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.662 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.337-38G>C		intron	N/A	NP_056093.3
	SASH1	NM_001346505.2		c.202-38G>C		intron	N/A	NP_001333434.1
	SASH1	NM_001346506.2		c.-101-38G>C		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.337-38G>C		intron	N/A	ENSP00000356437.3
	SASH1	ENST00000367469.5	TSL:3	n.255-38G>C		intron	N/A
	SASH1	ENST00000470750.1	TSL:3	n.-38G>C		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.422 AC: 63932 AN: 151476 Hom.: 13719 Cov.: 30

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.413

Gnomad SAS AF: 0.682

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.391

GnomAD2 exomes AF: 0.446 AC: 111954 AN: 251268 AF XY: 0.456

Gnomad AFR exome AF: 0.404

Gnomad AMR exome AF: 0.429

Gnomad ASJ exome AF: 0.429

Gnomad EAS exome AF: 0.425

Gnomad FIN exome AF: 0.459

Gnomad NFE exome AF: 0.400

Gnomad OTH exome AF: 0.419

GnomAD4 exome AF: 0.421 AC: 614296 AN: 1459534 Hom.: 132404 Cov.: 32 AF XY: 0.428 AC XY: 310633 AN XY: 726266

African (AFR) AF: 0.419 AC: 14015 AN: 33432

American (AMR) AF: 0.426 AC: 19056 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 11122 AN: 26128

East Asian (EAS) AF: 0.409 AC: 16248 AN: 39680

South Asian (SAS) AF: 0.663 AC: 57123 AN: 86218

European-Finnish (FIN) AF: 0.460 AC: 24578 AN: 53416

Middle Eastern (MID) AF: 0.419 AC: 2418 AN: 5768

European-Non Finnish (NFE) AF: 0.400 AC: 444248 AN: 1109858

Other (OTH) AF: 0.423 AC: 25488 AN: 60318

GnomAD4 genome AF: 0.422 AC: 63970 AN: 151594 Hom.: 13727 Cov.: 30 AF XY: 0.430 AC XY: 31832 AN XY: 74048

African (AFR) AF: 0.418 AC: 17290 AN: 41320

American (AMR) AF: 0.403 AC: 6147 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1475 AN: 3462

East Asian (EAS) AF: 0.414 AC: 2122 AN: 5130

South Asian (SAS) AF: 0.682 AC: 3259 AN: 4780

European-Finnish (FIN) AF: 0.454 AC: 4759 AN: 10490

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.406 AC: 27560 AN: 67876

Other (OTH) AF: 0.392 AC: 821 AN: 2096

Alfa AF: 0.421 Hom.: 2462

Bravo AF: 0.410

Asia WGS AF: 0.538 AC: 1870 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cancer, alopecia, pigment dyscrasia, onychodystrophy, and keratoderma Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dyschromatosis universalis hereditaria 1 Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.59
PhyloP100		1.9
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: rs2272998; hg19: chr6-148761456; COSMIC: COSV66562149; COSMIC: COSV66562149;