Variant chr19-49399142-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The ENST00000447857.8(KASH5):c.747G>A(p.Ala249Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,548,766 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 1 hom. )

Consequence

KASH5
ENST00000447857.8 splice_region, synonymous

Scores

Splicing: ADA: 0.9941

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 0.752

Variant links:

Genes affected

KASH5 (HGNC:26520): (KASH domain containing 5) Predicted to enable dynein complex binding activity. Predicted to be involved in several processes, including cytoskeleton organization; homologous chromosome segregation; and spindle localization. Predicted to act upstream of or within double-strand break repair via homologous recombination; oogenesis; and spermatogenesis. Predicted to be integral component of membrane. Predicted to be part of meiotic nuclear membrane microtubule tethering complex. Predicted to be active in chromosome; meiotic spindle pole; and nuclear outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

KASH5 links:

KASH5 (HGNC:):

KASH5 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-49399142-G-A is Pathogenic according to our data. Variant chr19-49399142-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1232307.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KASH5	NM_144688.5 linkuse as main transcript	c.747G>A	p.Ala249Ala	splice_region_variant, synonymous_variant	8/20	ENST00000447857.8	NP_653289.3	Q8N6L0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KASH5	ENST00000447857.8 linkuse as main transcript	c.747G>A	p.Ala249Ala	splice_region_variant, synonymous_variant	8/20	1	NM_144688.5	ENSP00000404220.2		Q8N6L0

Frequencies

GnomAD3 genomes

AF:

0.000999

AC:

152

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00194

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000689

AC:

104

AN:

151008

Hom.:

AF XY:

0.000673

AC XY:

AN XY:

80252

show subpopulations

Gnomad AFR exome

AF:

0.000253

Gnomad AMR exome

AF:

0.000127

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000939

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000129

Gnomad NFE exome

AF:

0.00163

Gnomad OTH exome

AF:

0.000234

GnomAD4 exome

AF:

0.00140

AC:

1954

AN:

1396442

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

918

AN XY:

688872

show subpopulations

Gnomad4 AFR exome

AF:

0.000159

Gnomad4 AMR exome

AF:

0.000144

Gnomad4 ASJ exome

AF:

0.0000399

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000508

Gnomad4 NFE exome

AF:

0.00173

Gnomad4 OTH exome

AF:

0.000882

GnomAD4 genome

AF:

0.000998

AC:

152

AN:

152324

Hom.:

Cov.:

AF XY:

0.000805

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00194

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00124

Hom.:

Bravo

AF:

0.000839

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Genetic non-acquired premature ovarian failure

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University

Sep 07, 2021

- -

Premature ovarian failure 22

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.85

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.23

Position offset: 25

DS_DL_spliceai

0.85

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over