16-87709348-T-C

Position:

• chr16-87709348-T-C

Variant summary

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

The NM_017566.4(KLHDC4):​c.1364A>G​(p.Asp455Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000197 in 152,168 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 33)
• Consequence: KLHDC4 NM_017566.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.81

Genes affected

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

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	UniProt
KLHDC4	NM_017566.4	c.1364A>G	p.Asp455Gly	missense_variant	10/12	ENST00000270583.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHDC4	ENST00000270583.10	c.1364A>G	p.Asp455Gly	missense_variant	10/12	1	NM_017566.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152168 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

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

Oct 04, 2022

The c.1364A>G (p.D455G) alteration is located in exon 10 (coding exon 10) of the KLHDC4 gene. This alteration results from a A to G substitution at nucleotide position 1364, causing the aspartic acid (D) at amino acid position 455 to be replaced by a glycine (G). 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	0.20
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	.;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	3.0	.;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.011	D;D;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		0.91	P;D;P
Vest4		0.69
MutPred		0.41		.;.;Loss of solvent accessibility (P = 0.1177);
MVP		0.78
MPC		0.042
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.51
gMVP		0.57

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

LitVar

Other links and lift over

dbSNP: rs1482795008; hg19: chr16-87742954;