rs759856682

Variant names:

• chr6-148343178-A-G
• rs759856682
• NM_015278.5:c.111A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-148343178-A-G
• chr6-148343178-A-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_015278.5(SASH1):​c.111A>G​(p.Thr37Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000269 in 1,600,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: SASH1 NM_015278.5 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.134
• 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: PanelApp Australia, 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, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-148343178-A-G is Benign according to our data. Variant chr6-148343178-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3051692.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.134 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000283 (41/1448096) while in subpopulation AMR AF = 0.000896 (40/44620). AF 95% confidence interval is 0.000677. There are 0 homozygotes in GnomAdExome4. There are 12 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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.111A>G	p.Thr37Thr	synonymous	Exon 1 of 20	NP_056093.3
	SASH1	NM_001346506.2		c.-327A>G		5_prime_UTR	Exon 1 of 21	NP_001333435.1
	SASH1	NM_001346505.2		c.22-46956A>G		intron	N/A	NP_001333434.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SASH1	ENST00000367467.8	TSL:1 MANE Select	c.111A>G	p.Thr37Thr	synonymous	Exon 1 of 20	ENSP00000356437.3	O94885
	SASH1	ENST00000946242.1		c.111A>G	p.Thr37Thr	synonymous	Exon 1 of 21	ENSP00000616301.1
	SASH1	ENST00000946243.1		c.111A>G	p.Thr37Thr	synonymous	Exon 1 of 21	ENSP00000616302.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000132 AC: 31 AN: 234522 AF XY: 0.0000622

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000910

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000283 AC: 41 AN: 1448096 Hom.: 0 Cov.: 32 AF XY: 0.0000166 AC XY: 12 AN XY: 720788

African (AFR) AF: 0.0000300 AC: 1 AN: 33386

American (AMR) AF: 0.000896 AC: 40 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 86064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111184

Other (OTH) AF: 0.00 AC: 0 AN: 60232

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.000131 AC: 2 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	SASH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.0
DANN	Benign	0.47
PhyloP100		0.13
PromoterAI		0.049	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs759856682; hg19: chr6-148664314;