Variant 14-49710303-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_172193.3(KLHDC1):c.326T>G(p.Ile109Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

KLHDC1
NM_172193.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.718

Variant links:

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]

KLHDC1 links:

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ACMG classification

Classification made for transcript

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=0.060453773).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLHDC1	NM_172193.3 linkuse as main transcript	c.326T>G	p.Ile109Ser	missense_variant	4/13	ENST00000359332.7
KLHDC1	XM_011536422.3 linkuse as main transcript	c.326T>G	p.Ile109Ser	missense_variant	4/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLHDC1	ENST00000359332.7 linkuse as main transcript	c.326T>G	p.Ile109Ser	missense_variant	4/13	1	NM_172193.3	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251336

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1459146

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726132

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000721

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2024

The c.326T>G (p.I109S) alteration is located in exon 4 (coding exon 4) of the KLHDC1 gene. This alteration results from a T to G substitution at nucleotide position 326, causing the isoleucine (I) at amino acid position 109 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

0.084

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.022

T;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.0096

MetaRNN

Benign

0.060

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.44

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.34

PROVEAN

Benign

0.10

N;.

REVEL

Benign

0.047

Sift

Benign

0.45

T;.

Sift4G

Benign

0.57

T;T

Polyphen

0.0050

B;.

Vest4

0.083

MutPred

0.44

Gain of catalytic residue at R104 (P = 0.0023);Gain of catalytic residue at R104 (P = 0.0023);

MVP

0.32

MPC

0.12

ClinPred

0.024

GERP RS

1.2

Varity_R

0.046

gMVP

0.41

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over