Genetic Variant KHDC4:p.Leu439Met (chr1-155917624-A-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.1315T>A(p.Leu439Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000172 in 1,450,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

KHDC4
NM_014949.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.236

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:

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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=0.11757472).

BS2

High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KHDC4	NM_014949.4 link	c.1315T>A	p.Leu439Met	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.1315T>A	p.Leu439Met	missense_variant	Exon 11 of 14	1	NM_014949.4	ENSP00000357304.3	Q7Z7F0-1
KHDC4	ENST00000368320.7 link	c.1315T>A	p.Leu439Met	missense_variant	Exon 11 of 13	1		ENSP00000357303.3	Q7Z7F0-2
KHDC4	ENST00000478002.5 link	n.554T>A		non_coding_transcript_exon_variant	Exon 5 of 8	5
KHDC4	ENST00000466520.1 link	n.-50T>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000363

AC:

AN:

220296

AF XY:

0.0000499

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000172

AC:

AN:

1450246

Hom.:

Cov.:

AF XY:

0.0000208

AC XY:

AN XY:

720888

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33218

American (AMR)

AF:

0.00

AC:

AN:

43500

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25752

East Asian (EAS)

AF:

0.00

AC:

AN:

39440

South Asian (SAS)

AF:

0.000234

AC:

AN:

85376

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51980

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4172

European-Non Finnish (NFE)

AF:

0.00000452

AC:

AN:

1107162

Other (OTH)

AF:

0.00

AC:

AN:

59646

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000416

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 26, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1315T>A (p.L439M) alteration is located in exon 11 (coding exon 11) of the KIAA0907 gene. This alteration results from a T to A substitution at nucleotide position 1315, causing the leucine (L) at amino acid position 439 to be replaced by a methionine (M). 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

0.065

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.035

T;.

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.0036

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-1.1

PhyloP100

0.24

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.25

N;N

REVEL

Benign

0.11

Sift

Benign

0.26

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.99

D;D

Vest4

0.31

MutPred

0.15

Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);

MVP

0.24

MPC

0.35

ClinPred

0.096

GERP RS

0.72

Varity_R

0.034

gMVP

0.029

Mutation Taster

=63/37

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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1-155917624-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over