rs200385590

Variant names:

• chr6-148390235-A-G
• rs200385590
• NM_015278.5:c.258A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_015278.5(SASH1):​c.258A>G​(p.Lys86Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,612,148 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: SASH1 NM_015278.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.184
• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 6-148390235-A-G is Benign according to our data. Variant chr6-148390235-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2656983.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.184 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000657 (100/152164) while in subpopulation NFE AF = 0.00116 (79/67994). AF 95% confidence interval is 0.000955. There are 0 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

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.258A>G	p.Lys86Lys	synonymous	Exon 2 of 20	NP_056093.3
	SASH1	NM_001346505.2		c.123A>G	p.Lys41Lys	synonymous	Exon 2 of 20	NP_001333434.1
	SASH1	NM_001346506.2		c.-180A>G		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.258A>G	p.Lys86Lys	synonymous	Exon 2 of 20	ENSP00000356437.3	O94885
	SASH1	ENST00000946242.1		c.258A>G	p.Lys86Lys	synonymous	Exon 2 of 21	ENSP00000616301.1
	SASH1	ENST00000946243.1		c.258A>G	p.Lys86Lys	synonymous	Exon 2 of 21	ENSP00000616302.1

Frequencies

GnomAD3 genomes AF: 0.000658 AC: 100 AN: 152046 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.000961

GnomAD2 exomes AF: 0.000697 AC: 175 AN: 251012 AF XY: 0.000693

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00149 AC: 2170 AN: 1459984 Hom.: 4 Cov.: 31 AF XY: 0.00145 AC XY: 1055 AN XY: 726320

African (AFR) AF: 0.000269 AC: 9 AN: 33428

American (AMR) AF: 0.000291 AC: 13 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86192

European-Finnish (FIN) AF: 0.000113 AC: 6 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4862

European-Non Finnish (NFE) AF: 0.00183 AC: 2030 AN: 1111506

Other (OTH) AF: 0.00126 AC: 76 AN: 60216

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.000645 AC XY: 48 AN XY: 74382

African (AFR) AF: 0.000337 AC: 14 AN: 41508

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 67994

Other (OTH) AF: 0.000951 AC: 2 AN: 2104

Alfa AF: 0.000731 Hom.: 0

Bravo AF: 0.000669

EpiCase AF: 0.00120

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	SASH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.7
DANN	Benign	0.68
PhyloP100		-0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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: rs200385590; hg19: chr6-148711371;