1-155921515-G-T

Variant names:

• chr1-155921515-G-T
• NM_014949.4:c.1126C>A

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.1126C>A​(p.Pro376Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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: 4.72

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=0.21374464).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KHDC4	NM_014949.4	c.1126C>A	p.Pro376Thr	missense_variant	Exon 10 of 14	ENST00000368321.8	NP_055764.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KHDC4	ENST00000368321.8	c.1126C>A	p.Pro376Thr	missense_variant	Exon 10 of 14	1	NM_014949.4	ENSP00000357304.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1126C>A (p.P376T) 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 1126, causing the proline (P) at amino acid position 376 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	0.088
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.041	T;.
Eigen	Benign	-0.0097
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		4.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.15
Sift	Benign	0.066	T;T
Sift4G	Uncertain	0.056	T;T
Polyphen		0.72	P;P
Vest4		0.49
MutPred		0.14		Gain of glycosylation at P376 (P = 0.0343);Gain of glycosylation at P376 (P = 0.0343);
MVP		0.16
MPC		0.71
ClinPred		0.76	D
GERP RS		5.6
Varity_R		0.20
gMVP		0.39
Mutation Taster		=77/23	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

Publications

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Other links and lift over

hg19: chr1-155891306;