Genetic Variant NM_014949.4:c.1300C>T (chr1-155917639-G-A) – 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_014949.4(KHDC4):c.1300C>T(p.Pro434Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,591,342 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P434L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

KHDC4
NM_014949.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.13

Publications

0 publications found

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 -4 ACMG points.

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KHDC4	NM_014949.4 link	c.1300C>T	p.Pro434Ser	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.1300C>T	p.Pro434Ser	missense_variant	Exon 11 of 14	1	NM_014949.4	ENSP00000357304.3	Q7Z7F0-1
KHDC4	ENST00000368320.7 link	c.1300C>T	p.Pro434Ser	missense_variant	Exon 11 of 13	1		ENSP00000357303.3	Q7Z7F0-2
KHDC4	ENST00000478002.5 link	n.539C>T		non_coding_transcript_exon_variant	Exon 5 of 8	5
KHDC4	ENST00000466520.1 link	n.-65C>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000480

AC:

AN:

208272

AF XY:

0.00000881

show subpopulations

Gnomad AFR exome

AF:

0.0000732

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000118

AC:

AN:

1439238

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

715040

show subpopulations

African (AFR)

AF:

0.000214

AC:

AN:

32654

American (AMR)

AF:

0.00

AC:

AN:

40504

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25276

East Asian (EAS)

AF:

0.00

AC:

AN:

39046

South Asian (SAS)

AF:

0.00

AC:

AN:

83968

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4144

European-Non Finnish (NFE)

AF:

0.00000816

AC:

AN:

1102982

Other (OTH)

AF:

0.0000169

AC:

AN:

59150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41404

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.00000834

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 19, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1300C>T (p.P434S) alteration is located in exon 11 (coding exon 11) of the KIAA0907 gene. This alteration results from a C to T substitution at nucleotide position 1300, causing the proline (P) at amino acid position 434 to be replaced by a serine (S). 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

0.075

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.0081

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Benign

-1.1

PhyloP100

9.1

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.7

D;N

REVEL

Benign

0.16

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.013

D;D

Polyphen

0.88

P;P

Vest4

0.73

MutPred

0.22

Gain of phosphorylation at P434 (P = 0.0458);Gain of phosphorylation at P434 (P = 0.0458);

MVP

0.11

MPC

1.1

ClinPred

0.81

GERP RS

5.8

Varity_R

0.31

gMVP

0.25

Mutation Taster

=65/35

polymorphism

(source)

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

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NM_014949.4:c.1300C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over