dbSNP rs540646386: KHDC4:p.Ala432Thr (chr1-155917645-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_014949.4(KHDC4):c.1294G>A(p.Ala432Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000504 in 1,586,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

KHDC4
NM_014949.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.32

Variant links:

Genes affected

KHDC4 (HGNC:29145): (KH domain containing 4, pre-mRNA splicing factor) Enables RNA binding activity. Involved in mRNA splice site selection. Located in cytoplasm and nucleoplasm. Colocalizes with spliceosomal complex. [provided by Alliance of Genome Resources, Apr 2022]

KHDC4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24475625).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KHDC4	NM_014949.4 link	c.1294G>A	p.Ala432Thr	missense_variant	Exon 11 of 14	ENST00000368321.8	NP_055764.2	Q7Z7F0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KHDC4	ENST00000368321.8 link	c.1294G>A	p.Ala432Thr	missense_variant	Exon 11 of 14	1	NM_014949.4	ENSP00000357304.3	Q7Z7F0-1
KHDC4	ENST00000368320.7 link	c.1294G>A	p.Ala432Thr	missense_variant	Exon 11 of 13	1		ENSP00000357303.3	Q7Z7F0-2
KHDC4	ENST00000478002.5 link	n.533G>A		non_coding_transcript_exon_variant	Exon 5 of 8	5
KHDC4	ENST00000466520.1 link	n.-71G>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000694

AC:

AN:

201764

AF XY:

0.0000730

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000920

Gnomad OTH exome

AF:

0.000198

GnomAD4 exome

AF:

0.0000516

AC:

AN:

1434742

Hom.:

Cov.:

AF XY:

0.0000407

AC XY:

AN XY:

712496

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32528

American (AMR)

AF:

0.00

AC:

AN:

39674

Ashkenazi Jewish (ASJ)

AF:

0.000160

AC:

AN:

25066

East Asian (EAS)

AF:

0.00

AC:

AN:

38824

South Asian (SAS)

AF:

0.000336

AC:

AN:

83436

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51306

Middle Eastern (MID)

AF:

0.000243

AC:

AN:

4118

European-Non Finnish (NFE)

AF:

0.0000282

AC:

AN:

1100808

Other (OTH)

AF:

0.000170

AC:

AN:

58982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000904

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000836

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 04, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1294G>A (p.A432T) alteration is located in exon 11 (coding exon 11) of the KIAA0907 gene. This alteration results from a G to A substitution at nucleotide position 1294, causing the alanine (A) at amino acid position 432 to be replaced by a threonine (T). 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

0.072

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

T;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.0025

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-1.0

PhyloP100

3.3

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.88

N;N

REVEL

Benign

0.19

Sift

Benign

0.20

T;T

Sift4G

Benign

0.40

T;T

Polyphen

0.97

D;D

Vest4

0.62

MVP

0.20

MPC

0.42

ClinPred

0.11

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.084

gMVP

0.050

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

rs540646386

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over