Genetic Variant SASH1:p.Glu39Gln (chr6-148343182-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015278.5(SASH1):c.115G>C(p.Glu39Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E39K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SASH1
NM_015278.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.22

Publications

0 publications found

Variant links:

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

SASH1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19189054).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SASH1	NM_015278.5	MANE Select	c.115G>C	p.Glu39Gln	missense	Exon 1 of 20	NP_056093.3
SASH1	NM_001346506.2		c.-323G>C		5_prime_UTR	Exon 1 of 21	NP_001333435.1
SASH1	NM_001346505.2		c.22-46952G>C		intron	N/A	NP_001333434.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SASH1	ENST00000367467.8	TSL:1 MANE Select	c.115G>C	p.Glu39Gln	missense	Exon 1 of 20	ENSP00000356437.3	O94885
SASH1	ENST00000946242.1		c.115G>C	p.Glu39Gln	missense	Exon 1 of 21	ENSP00000616301.1
SASH1	ENST00000946243.1		c.115G>C	p.Glu39Gln	missense	Exon 1 of 21	ENSP00000616302.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

234702

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1447982

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720740

African (AFR)

AF:

0.00

AC:

AN:

33380

American (AMR)

AF:

0.00

AC:

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39604

South Asian (SAS)

AF:

0.00

AC:

AN:

86058

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41082

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111152

Other (OTH)

AF:

0.00

AC:

AN:

60234

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0098

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.59

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PhyloP100

4.2

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.60

REVEL

Benign

0.095

Sift

Uncertain

0.011

Sift4G

Benign

0.070

Polyphen

0.80

Vest4

0.22

MutPred

0.11

Gain of MoRF binding (P = 0.0519)

MVP

0.59

MPC

0.17

ClinPred

0.52

GERP RS

4.1

PromoterAI

-0.090

Neutral

(source)

Varity_R

0.13

gMVP

0.30

Mutation Taster

=96/4

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over