6-148343146-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_015278.5(SASH1):c.79C>G(p.Pro27Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000932 in 1,598,850 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P27R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00096 ( 1 hom. )

Consequence

SASH1
NM_015278.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0620

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: 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

SASH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008150458).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000618 (94/152204) while in subpopulation NFE AF = 0.001 (68/67980). AF 95% confidence interval is 0.000809. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.79C>G	p.Pro27Ala	missense	Exon 1 of 20	NP_056093.3
SASH1	NM_001346506.2		c.-359C>G		5_prime_UTR	Exon 1 of 21	NP_001333435.1
SASH1	NM_001346505.2		c.22-46988C>G		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.79C>G	p.Pro27Ala	missense	Exon 1 of 20	ENSP00000356437.3	O94885
SASH1	ENST00000946242.1		c.79C>G	p.Pro27Ala	missense	Exon 1 of 21	ENSP00000616301.1
SASH1	ENST00000946243.1		c.79C>G	p.Pro27Ala	missense	Exon 1 of 21	ENSP00000616302.1

Frequencies

GnomAD3 genomes

AF:

0.000618

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00100

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000586

AC:

135

AN:

230294

AF XY:

0.000567

show subpopulations

Gnomad AFR exome

AF:

0.0000693

Gnomad AMR exome

AF:

0.000236

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000164

Gnomad NFE exome

AF:

0.00112

Gnomad OTH exome

AF:

0.000864

GnomAD4 exome

AF:

0.000965

AC:

1396

AN:

1446646

Hom.:

Cov.:

AF XY:

0.000943

AC XY:

679

AN XY:

720044

show subpopulations

African (AFR)

AF:

0.000270

AC:

AN:

33350

American (AMR)

AF:

0.000336

AC:

AN:

44588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26068

East Asian (EAS)

AF:

0.00

AC:

AN:

39590

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85942

European-Finnish (FIN)

AF:

0.000223

AC:

AN:

40390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00118

AC:

1307

AN:

1110830

Other (OTH)

AF:

0.000915

AC:

AN:

60134

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

165

248

330

413

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.000618

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.000699

AC XY:

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41572

American (AMR)

AF:

0.000915

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000284

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00100

AC:

AN:

67980

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.000646

Hom.:

Bravo

AF:

0.000759

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000816

AC:

ExAC

AF:

0.000638

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.00101

ClinVar

ClinVar submissions

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

Benign

0.061

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.0087

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0084

LIST_S2

Benign

0.37

M_CAP

Benign

0.022

MetaRNN

Benign

0.0082

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.69

PhyloP100

0.062

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.39

REVEL

Benign

0.030

Sift

Benign

1.0

Sift4G

Benign

0.076

Polyphen

0.015

Vest4

0.17

MVP

0.16

MPC

0.14

ClinPred

0.011

GERP RS

2.0

PromoterAI

-0.050

Neutral

(source)

Varity_R

0.054

gMVP

0.15

Mutation Taster

=99/1

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