Genetic Variant KHDRBS3:p.His22Tyr (chr8-135457930-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006558.3(KHDRBS3):c.64C>T(p.His22Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,449,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

KHDRBS3
NM_006558.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.85

Publications

0 publications found

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:

ENSG00000306757 (HGNC:):

ENSG00000306757 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KHDRBS3	NM_006558.3 link	c.64C>T	p.His22Tyr	missense_variant	Exon 1 of 9	ENST00000355849.10	NP_006549.1	O75525-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KHDRBS3	ENST00000355849.10 link	c.64C>T	p.His22Tyr	missense_variant	Exon 1 of 9	1	NM_006558.3	ENSP00000348108.5	O75525-1
KHDRBS3	ENST00000704572.1 link	c.436C>T	p.His146Tyr	missense_variant	Exon 1 of 9			ENSP00000515947.1	A0A994J7I5
ENSG00000306757	ENST00000820829.1 link	n.27G>A		non_coding_transcript_exon_variant	Exon 1 of 3
KHDRBS3	ENST00000524199.5 link	c.-250C>T		upstream_gene_variant		5		ENSP00000431022.1	E5RJZ9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1449876

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

720604

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32650

American (AMR)

AF:

0.00

AC:

AN:

43980

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25738

East Asian (EAS)

AF:

0.00

AC:

AN:

38912

South Asian (SAS)

AF:

0.00

AC:

AN:

84482

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51638

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.0000163

AC:

AN:

1107018

Other (OTH)

AF:

0.00

AC:

AN:

59756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 03, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.64C>T (p.H22Y) alteration is located in exon 1 (coding exon 1) of the KHDRBS3 gene. This alteration results from a C to T substitution at nucleotide position 64, causing the histidine (H) at amino acid position 22 to be replaced by a tyrosine (Y). 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

Pathogenic

0.83

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.58

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.75

MetaRNN

Uncertain

0.59

MetaSVM

Benign

-0.48

MutationAssessor

Pathogenic

3.1

PhyloP100

4.9

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.26

Sift

Benign

0.069

Sift4G

Benign

1.0

Polyphen

0.51

Vest4

0.41

MutPred

0.45

Gain of phosphorylation at H22 (P = 0.0458);

MVP

0.69

MPC

1.4

ClinPred

0.68

GERP RS

2.8

PromoterAI

0.096

Neutral

(source)

Varity_R

0.63

gMVP

0.78

Mutation Taster

=60/40

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over