Variant chr8-135457882-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006558.3(KHDRBS3):c.16C>G(p.Leu6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,595,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

KHDRBS3
NM_006558.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.97

Variant links:

Genes affected

KHDRBS3 (HGNC:18117): (KH RNA binding domain containing, signal transduction associated 3) Enables RNA binding activity; identical protein binding activity; and protein domain specific binding activity. Predicted to be involved in regulation of alternative mRNA splicing, via spliceosome and spermatogenesis. Located in nucleoplasm. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

KHDRBS3 links:

KHDRBS3 (HGNC:):

KHDRBS3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1800963).

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KHDRBS3	NM_006558.3 linkuse as main transcript	c.16C>G	p.Leu6Val	missense_variant	1/9	ENST00000355849.10	NP_006549.1	O75525-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KHDRBS3	ENST00000355849.10 linkuse as main transcript	c.16C>G	p.Leu6Val	missense_variant	1/9	1	NM_006558.3	ENSP00000348108.5		O75525-1
KHDRBS3	ENST00000704572.1 linkuse as main transcript	c.388C>G	p.Leu130Val	missense_variant	1/9			ENSP00000515947.1		A0A994J7I5

Frequencies

GnomAD3 genomes

AF:

0.0000923

AC:

AN:

151656

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0000655

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:

0.000133

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000904

AC:

AN:

221200

Hom.:

AF XY:

0.0000909

AC XY:

AN XY:

120984

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000152

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000153

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000184

AC:

265

AN:

1443840

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

110

AN XY:

717504

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000161

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000230

Gnomad4 OTH exome

AF:

0.0000672

GnomAD4 genome

AF:

0.0000923

AC:

AN:

151656

Hom.:

Cov.:

AF XY:

0.0000810

AC XY:

AN XY:

74058

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000133

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000913

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 07, 2024

The c.16C>G (p.L6V) alteration is located in exon 1 (coding exon 1) of the KHDRBS3 gene. This alteration results from a C to G substitution at nucleotide position 16, causing the leucine (L) at amino acid position 6 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.40

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

Eigen

Benign

-0.045

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.74

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.2

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.2

REVEL

Benign

0.20

Sift

Benign

0.34

Sift4G

Benign

0.35

Polyphen

0.94

Vest4

0.21

MVP

0.69

MPC

1.1

ClinPred

0.13

GERP RS

1.3

Varity_R

0.41

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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