Genetic Variant KHDRBS1:p.Asp415Asn (chr1-32042535-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

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

The NM_006559.3(KHDRBS1):c.1243G>A(p.Asp415Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000781 in 1,612,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

KHDRBS1
NM_006559.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.33

Variant links:

Genes affected

KHDRBS1 (HGNC:18116): (KH RNA binding domain containing, signal transduction associated 1) This gene encodes a member of the K homology domain-containing, RNA-binding, signal transduction-associated protein family. The encoded protein appears to have many functions and may be involved in a variety of cellular processes, including alternative splicing, cell cycle regulation, RNA 3'-end formation, tumorigenesis, and regulation of human immunodeficiency virus gene expression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

KHDRBS1 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=0.14204893).

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KHDRBS1	NM_006559.3 link	c.1243G>A	p.Asp415Asn	missense_variant	Exon 9 of 9	ENST00000327300.12	NP_006550.1	Q07666-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KHDRBS1	ENST00000327300.12 link	c.1243G>A	p.Asp415Asn	missense_variant	Exon 9 of 9	1	NM_006559.3	ENSP00000313829.7	Q07666-1
KHDRBS1	ENST00000492989.1 link	c.1126G>A	p.Asp376Asn	missense_variant	Exon 8 of 8	1		ENSP00000417731.1	Q07666-3
KHDRBS1	ENST00000307714.12 link	n.1396G>A		non_coding_transcript_exon_variant	Exon 9 of 9	1
KHDRBS1	ENST00000484270.2 link	n.1057G>A		non_coding_transcript_exon_variant	Exon 9 of 11	5

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000132

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000679

AC:

AN:

250494

Hom.:

AF XY:

0.0000960

AC XY:

AN XY:

135416

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000767

AC:

112

AN:

1460424

Hom.:

Cov.:

AF XY:

0.0000647

AC XY:

AN XY:

726616

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000945

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000778

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1243G>A (p.D415N) alteration is located in exon 9 (coding exon 9) of the KHDRBS1 gene. This alteration results from a G to A substitution at nucleotide position 1243, causing the aspartic acid (D) at amino acid position 415 to be replaced by an asparagine (N). 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

0.23

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.59

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.84

T;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.98

L;.

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.082

Sift

Benign

0.10

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.0020

B;B

Vest4

0.17

MVP

0.52

MPC

2.1

ClinPred

0.11

GERP RS

4.0

Varity_R

0.075

gMVP

0.49

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

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