rs755332259

Variant names:

• chr1-155917639-G-A
• rs755332259
• NM_014949.4:c.1300C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_014949.4(KHDC4):​c.1300C>T​(p.Pro434Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,591,342 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P434L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: KHDC4 NM_014949.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.13
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KHDC4	NM_014949.4	c.1300C>T	p.Pro434Ser	missense_variant	Exon 11 of 14	ENST00000368321.8	NP_055764.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KHDC4	ENST00000368321.8	c.1300C>T	p.Pro434Ser	missense_variant	Exon 11 of 14	1	NM_014949.4	ENSP00000357304.3
KHDC4	ENST00000368320.7	c.1300C>T	p.Pro434Ser	missense_variant	Exon 11 of 13	1		ENSP00000357303.3
KHDC4	ENST00000478002.5	n.539C>T		non_coding_transcript_exon_variant	Exon 5 of 8	5
KHDC4	ENST00000466520.1	n.-65C>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000480 AC: 1 AN: 208272 AF XY: 0.00000881

Gnomad AFR exome AF: 0.0000732

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: 0.0000118 AC: 17 AN: 1439238 Hom.: 0 Cov.: 33 AF XY: 0.0000140 AC XY: 10 AN XY: 715040

African (AFR) AF: 0.000214 AC: 7 AN: 32654

American (AMR) AF: 0.00 AC: 0 AN: 40504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25276

East Asian (EAS) AF: 0.00 AC: 0 AN: 39046

South Asian (SAS) AF: 0.00 AC: 0 AN: 83968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4144

European-Non Finnish (NFE) AF: 0.00000816 AC: 9 AN: 1102982

Other (OTH) AF: 0.0000169 AC: 1 AN: 59150

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74296

African (AFR) AF: 0.0000725 AC: 3 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.00000834 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1300C>T (p.P434S) alteration is located in exon 11 (coding exon 11) of the KIAA0907 gene. This alteration results from a C to T substitution at nucleotide position 1300, causing the proline (P) at amino acid position 434 to be replaced by a serine (S). 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	0.075
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.0081	T
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-1.1	T
PhyloP100		9.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.7	D;N
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.88	P;P
Vest4		0.73
MutPred		0.22		Gain of phosphorylation at P434 (P = 0.0458);Gain of phosphorylation at P434 (P = 0.0458);
MVP		0.11
MPC		1.1
ClinPred		0.81	D
GERP RS		5.8
Varity_R		0.31
gMVP		0.25
Mutation Taster		=65/35	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: rs755332259; hg19: chr1-155887430;