16-87755258-G-C

Variant names:

• chr16-87755258-G-C
• rs2303771
• NM_017566.4:c.305C>G

Variant summary

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

The NM_017566.4(KLHDC4):​c.305C>G​(p.Thr102Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KLHDC4 NM_017566.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.37
• Publications: 0 publications found

Genes affected

KLHDC4 (HGNC:25272): (kelch domain containing 4)

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=0.24250925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHDC4	NM_017566.4	c.305C>G	p.Thr102Ser	missense_variant	Exon 4 of 12	ENST00000270583.10	NP_060036.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHDC4	ENST00000270583.10	c.305C>G	p.Thr102Ser	missense_variant	Exon 4 of 12	1	NM_017566.4	ENSP00000270583.4
KLHDC4	ENST00000567298.5	n.305C>G		non_coding_transcript_exon_variant	Exon 4 of 17	5		ENSP00000457570.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455122 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724246

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33312

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106030

Other (OTH) AF: 0.00 AC: 0 AN: 60152

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.0058	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.0070	.;.;T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.55	.;N;N;.
PhyloP100		4.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;.
Polyphen		0.66	P;P;B;.
Vest4		0.34
MutPred		0.50		.;Loss of phosphorylation at T102 (P = 0.0309);Loss of phosphorylation at T102 (P = 0.0309);.;
MVP		0.44
MPC		0.031
ClinPred		0.66	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.52
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2303771; hg19: chr16-87788864;