chr6-148390236-C-A

Variant names:

• chr6-148390236-C-A
• rs563008779
• NM_015278.5:c.259C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015278.5(SASH1):​c.259C>A​(p.Arg87Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.000000685 in 1,459,918 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SASH1 NM_015278.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.63
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SASH1	NM_015278.5	MANE Select	c.259C>A	p.Arg87Arg	synonymous	Exon 2 of 20	NP_056093.3
	SASH1	NM_001346505.2		c.124C>A	p.Arg42Arg	synonymous	Exon 2 of 20	NP_001333434.1
	SASH1	NM_001346506.2		c.-179C>A		5_prime_UTR	Exon 2 of 21	NP_001333435.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SASH1	ENST00000367467.8	TSL:1 MANE Select	c.259C>A	p.Arg87Arg	synonymous	Exon 2 of 20	ENSP00000356437.3	O94885
	SASH1	ENST00000946242.1		c.259C>A	p.Arg87Arg	synonymous	Exon 2 of 21	ENSP00000616301.1
	SASH1	ENST00000946243.1		c.259C>A	p.Arg87Arg	synonymous	Exon 2 of 21	ENSP00000616302.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459918 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726284

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4846

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111450

Other (OTH) AF: 0.00 AC: 0 AN: 60218

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	12
DANN	Benign	0.76
PhyloP100		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs563008779; hg19: chr6-148711372;