NM_014949.4:c.1808G>A

Variant names:

• chr1-155914158-C-T
• rs781098786
• NM_014949.4:c.1808G>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.1808G>A​(p.Arg603Gln) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KHDC4 NM_014949.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.81
• 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=0.26321524).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KHDC4	NM_014949.4	c.1808G>A	p.Arg603Gln	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.1808G>A	p.Arg603Gln	missense_variant	Exon 14 of 14	1	NM_014949.4	ENSP00000357304.3
KHDC4	ENST00000368320.7	c.*1665G>A		3_prime_UTR_variant	Exon 13 of 13	1		ENSP00000357303.3
KHDC4	ENST00000478002.5	n.1019G>A		non_coding_transcript_exon_variant	Exon 8 of 8	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1808G>A (p.R603Q) alteration is located in exon 14 (coding exon 14) of the KIAA0907 gene. This alteration results from a G to A substitution at nucleotide position 1808, causing the arginine (R) at amino acid position 603 to be replaced by a glutamine (Q). 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	0.10
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.022	T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.66	T
PhyloP100		2.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.26
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.17
MutPred		0.19		Loss of loop (P = 0.0073);
MVP		0.26
MPC		1.2
ClinPred		0.74	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.17
Mutation Taster		=57/43	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

dbSNP: rs781098786; hg19: chr1-155883949;