1-155914189-A-C

Variant names:

• chr1-155914189-A-C
• NM_014949.4:c.1777T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014949.4(KHDC4):​c.1777T>G​(p.Leu593Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 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)
• Consequence: KHDC4 NM_014949.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11317626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KHDC4	NM_014949.4	c.1777T>G	p.Leu593Val	missense_variant	Exon 14 of 14	ENST00000368321.8	NP_055764.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KHDC4	ENST00000368321.8	c.1777T>G	p.Leu593Val	missense_variant	Exon 14 of 14	1	NM_014949.4	ENSP00000357304.3
KHDC4	ENST00000368320.7	c.*1634T>G		3_prime_UTR_variant	Exon 13 of 13	1		ENSP00000357303.3
KHDC4	ENST00000478002.5	n.988T>G		non_coding_transcript_exon_variant	Exon 8 of 8	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1777T>G (p.L593V) alteration is located in exon 14 (coding exon 14) of the KIAA0907 gene. This alteration results from a T to G substitution at nucleotide position 1777, causing the leucine (L) at amino acid position 593 to be replaced by a valine (V). 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	0.070
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.073
Sift	Uncertain	0.022	D
Sift4G	Benign	0.57	T
Polyphen		0.60	P
Vest4		0.36
MutPred		0.13		Gain of MoRF binding (P = 0.0877);
MVP		0.18
MPC		0.44
ClinPred		0.15	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.046
gMVP		0.11
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

hg19: chr1-155883980;