Genetic Variant SASH3:c.442+99T>G (chrX-129791180-T-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_018990.4(SASH3):c.442+99T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 913,711 control chromosomes in the GnomAD database, including 25,639 homozygotes. There are 71,973 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.26 ( 2747 hom., 8593 hem., cov: 23)

Exomes 𝑓: 0.28 ( 22892 hom. 63380 hem. )

Consequence

SASH3
NM_018990.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.00400

Publications

2 publications found

Variant links:

Genes affected

SASH3 (HGNC:15975): (SAM and SH3 domain containing 3) The protein encoded by this gene contains a Src homology-3 (SH3) domain and a sterile alpha motif (SAM), both of which are found in proteins involved in cell signaling. This protein may function as a signaling adapter protein in lymphocytes.[provided by RefSeq, Sep 2009]

SASH3 Gene-Disease associations (from GenCC):

immunodeficiency 102
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
combined immunodeficiency, X-linked
Inheritance: XL Classification: STRONG Submitted by: ClinGen

SASH3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant X-129791180-T-G is Benign according to our data. Variant chrX-129791180-T-G is described in ClinVar as [Benign]. Clinvar id is 2688304.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SASH3	NM_018990.4 link	c.442+99T>G		intron_variant	Intron 4 of 7	ENST00000356892.4	NP_061863.1	O75995
SASH3	XM_006724763.1 link	c.442+99T>G		intron_variant	Intron 4 of 6		XP_006724826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SASH3	ENST00000356892.4 link	c.442+99T>G		intron_variant	Intron 4 of 7	1	NM_018990.4	ENSP00000349359.3		O75995

Frequencies

GnomAD3 genomes

AF:

0.258

AC:

28660

AN:

111241

Hom.:

2746

Cov.:

show subpopulations

Gnomad AFR

AF:

0.198

Gnomad AMI

AF:

0.446

Gnomad AMR

AF:

0.426

Gnomad ASJ

AF:

0.191

Gnomad EAS

AF:

0.190

Gnomad SAS

AF:

0.265

Gnomad FIN

AF:

0.281

Gnomad MID

AF:

0.325

Gnomad NFE

AF:

0.260

Gnomad OTH

AF:

0.277

GnomAD4 exome

AF:

0.284

AC:

227516

AN:

802413

Hom.:

22892

AF XY:

0.315

AC XY:

63380

AN XY:

201155

show subpopulations

African (AFR)

AF:

0.213

AC:

4227

AN:

19856

American (AMR)

AF:

0.528

AC:

13630

AN:

25815

Ashkenazi Jewish (ASJ)

AF:

0.183

AC:

2581

AN:

14084

East Asian (EAS)

AF:

0.184

AC:

5149

AN:

28011

South Asian (SAS)

AF:

0.288

AC:

11469

AN:

39844

European-Finnish (FIN)

AF:

0.295

AC:

11044

AN:

37416

Middle Eastern (MID)

AF:

0.270

AC:

588

AN:

2176

European-Non Finnish (NFE)

AF:

0.282

AC:

169068

AN:

599401

Other (OTH)

AF:

0.273

AC:

9760

AN:

35810

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

5829

11659

17488

23318

29147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.258

AC:

28675

AN:

111298

Hom.:

2747

Cov.:

AF XY:

0.256

AC XY:

8593

AN XY:

33528

show subpopulations

African (AFR)

AF:

0.198

AC:

6079

AN:

30679

American (AMR)

AF:

0.427

AC:

4501

AN:

10542

Ashkenazi Jewish (ASJ)

AF:

0.191

AC:

504

AN:

2636

East Asian (EAS)

AF:

0.189

AC:

667

AN:

3529

South Asian (SAS)

AF:

0.266

AC:

716

AN:

2687

European-Finnish (FIN)

AF:

0.281

AC:

1662

AN:

5922

Middle Eastern (MID)

AF:

0.324

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.260

AC:

13759

AN:

52898

Other (OTH)

AF:

0.275

AC:

418

AN:

1519

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

772

1544

2316

3088

3860

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.261

Hom.:

16247

Bravo

AF:

0.268

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 25% of patients studied by a panel of primary immunodeficiencies. Number of patients: 24. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

5.5

(source)

DANN

Benign

0.70

PhyloP100

0.0040

Mutation Taster

=100/0

polymorphism (auto)

(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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X-129791180-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over