1-155921617-G-T

Position:

• chr1-155921617-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014949.4(KHDC4):​c.1024C>A​(p.Pro342Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,254 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KHDC4 NM_014949.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.15

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KHDC4	NM_014949.4	c.1024C>A	p.Pro342Thr	missense_variant	10/14	ENST00000368321.8	NP_055764.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KHDC4	ENST00000368321.8	c.1024C>A	p.Pro342Thr	missense_variant	10/14	1	NM_014949.4	ENSP00000357304.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461254 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726794

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2023

The c.1024C>A (p.P342T) alteration is located in exon 10 (coding exon 10) of the KIAA0907 gene. This alteration results from a C to A substitution at nucleotide position 1024, causing the proline (P) at amino acid position 342 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	0.078
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.66	T
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.4	N;D
REVEL	Uncertain	0.33
Sift	Benign	0.042	D;T
Sift4G	Benign	0.071	T;T
Polyphen		1.0	D;D
Vest4		0.76
MutPred		0.46		Gain of glycosylation at P342 (P = 0.0259);Gain of glycosylation at P342 (P = 0.0259);
MVP		0.24
MPC		1.2
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.34
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1673865500; hg19: chr1-155891408;