chr6-148343215-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_015278.5(SASH1):c.148G>C(p.Gly50Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000321 in 1,587,312 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

SASH1
NM_015278.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.86

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000321 (46/1435164) while in subpopulation AMR AF = 0.00103 (45/43758). AF 95% confidence interval is 0.000789. There are 0 homozygotes in GnomAdExome4. There are 16 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.148G>C	p.Gly50Arg	missense	Exon 1 of 20	NP_056093.3
SASH1	NM_001346506.2		c.-290G>C		5_prime_UTR	Exon 1 of 21	NP_001333435.1
SASH1	NM_001346505.2		c.22-46919G>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.148G>C	p.Gly50Arg	missense	Exon 1 of 20	ENSP00000356437.3	O94885
SASH1	ENST00000946242.1		c.148G>C	p.Gly50Arg	missense	Exon 1 of 21	ENSP00000616301.1
SASH1	ENST00000946243.1		c.148G>C	p.Gly50Arg	missense	Exon 1 of 21	ENSP00000616302.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.000156

AC:

AN:

223868

AF XY:

0.000122

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00106

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:

0.000181

GnomAD4 exome

AF:

0.0000321

AC:

AN:

1435164

Hom.:

Cov.:

AF XY:

0.0000224

AC XY:

AN XY:

713688

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32716

American (AMR)

AF:

0.00103

AC:

AN:

43758

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25856

East Asian (EAS)

AF:

0.00

AC:

AN:

38616

South Asian (SAS)

AF:

0.00

AC:

AN:

84760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40044

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104084

Other (OTH)

AF:

0.0000168

AC:

AN:

59604

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.000327

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000742

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.061

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

5.9

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.30

Sift

Benign

0.065

Sift4G

Benign

0.083

Polyphen

1.0

Vest4

0.81

MutPred

0.51

Gain of MoRF binding (P = 0.0066)

MVP

0.52

MPC

0.37

ClinPred

0.094

GERP RS

5.0

PromoterAI

0.086

Neutral

(source)

Varity_R

0.44

gMVP

0.45

Mutation Taster

=75/25

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over