14-49693203-C-G

Position:

• chr14-49693203-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_172193.3(KLHDC1):​c.9C>G​(p.Asp3Glu) 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. 14/21 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: 33)
• Consequence: KLHDC1 NM_172193.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.289

Genes affected

KLHDC1 (HGNC:19836): (kelch domain containing 1) Enables ubiquitin ligase-substrate adaptor activity. Involved in ubiquitin-dependent protein catabolic process via the C-end degron rule pathway. Is active in Cul5-RING ubiquitin ligase complex and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050400615).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHDC1	NM_172193.3	c.9C>G	p.Asp3Glu	missense_variant	1/13	ENST00000359332.7	NP_751943.1
KLHDC1	XM_011536422.3	c.9C>G	p.Asp3Glu	missense_variant	1/13		XP_011534724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHDC1	ENST00000359332.7	c.9C>G	p.Asp3Glu	missense_variant	1/13	1	NM_172193.3	ENSP00000352282.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Jul 27, 2024

The c.9C>G (p.D3E) alteration is located in exon 1 (coding exon 1) of the KLHDC1 gene. This alteration results from a C to G substitution at nucleotide position 9, causing the aspartic acid (D) at amino acid position 3 to be replaced by a glutamic acid (E). 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	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.70
DEOGEN2	Benign	0.019	T;.;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.54	T;T;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.050	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.14	N;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.31	N;N;N
REVEL	Benign	0.026
Sift	Benign	0.061	T;T;T
Sift4G	Benign	0.78	T;T;T
Polyphen		0.083	B;.;.
Vest4		0.39
MutPred		0.27		Gain of catalytic residue at Q5 (P = 0.0472);Gain of catalytic residue at Q5 (P = 0.0472);Gain of catalytic residue at Q5 (P = 0.0472);
MVP		0.22
MPC		0.092
ClinPred		0.095	T
GERP RS		0.94
Varity_R		0.070
gMVP		0.23

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-50159921;