6-148343194-C-G

Variant names:

• chr6-148343194-C-G
• rs764725698
• NM_015278.5:c.127C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_015278.5(SASH1):​c.127C>G​(p.Arg43Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000415 in 1,447,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SASH1 NM_015278.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.435
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24083287).

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.127C>G	p.Arg43Gly	missense	Exon 1 of 20	NP_056093.3
	SASH1	NM_001346506.2		c.-311C>G		5_prime_UTR	Exon 1 of 21	NP_001333435.1
	SASH1	NM_001346505.2		c.22-46940C>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.127C>G	p.Arg43Gly	missense	Exon 1 of 20	ENSP00000356437.3	O94885
	SASH1	ENST00000946242.1		c.127C>G	p.Arg43Gly	missense	Exon 1 of 21	ENSP00000616301.1
	SASH1	ENST00000946243.1		c.127C>G	p.Arg43Gly	missense	Exon 1 of 21	ENSP00000616302.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000426 AC: 1 AN: 234830 AF XY: 0.00000777

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

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: 0.00000415 AC: 6 AN: 1447326 Hom.: 0 Cov.: 32 AF XY: 0.00000833 AC XY: 6 AN XY: 720356

African (AFR) AF: 0.00 AC: 0 AN: 33352

American (AMR) AF: 0.0000449 AC: 2 AN: 44584

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110790

Other (OTH) AF: 0.00 AC: 0 AN: 60192

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.43
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.23
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.32	T
Polyphen		0.0020	B
Vest4		0.63
MutPred		0.33		Loss of helix (P = 0.0237)
MVP		0.29
MPC		0.25
ClinPred		0.14	T
GERP RS		-1.4
PromoterAI		0.032	Neutral
Varity_R		0.11
gMVP		0.21
Mutation Taster		=95/5	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: rs764725698; hg19: chr6-148664330;