1-161098758-G-T

Variant names:

• chr1-161098758-G-T
• NM_152366.5:c.223G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152366.5(KLHDC9):​c.223G>T​(p.Gly75Cys) 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. 12/21 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KLHDC9 NM_152366.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

Genes affected

KLHDC9 (HGNC:28489): (kelch domain containing 9) Enables cyclin binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28043127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHDC9	NM_152366.5	c.223G>T	p.Gly75Cys	missense_variant	Exon 1 of 4	ENST00000368011.9	NP_689579.3
KLHDC9	NM_001007255.3	c.223G>T	p.Gly75Cys	missense_variant	Exon 1 of 4		NP_001007256.1
KLHDC9	NR_033385.2	n.137G>T		non_coding_transcript_exon_variant	Exon 2 of 5
KLHDC9	NR_033386.2	n.137G>T		non_coding_transcript_exon_variant	Exon 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHDC9	ENST00000368011.9	c.223G>T	p.Gly75Cys	missense_variant	Exon 1 of 4	1	NM_152366.5	ENSP00000356990.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1451078 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720976

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.223G>T (p.G75C) alteration is located in exon 1 (coding exon 1) of the KLHDC9 gene. This alteration results from a G to T substitution at nucleotide position 223, causing the glycine (G) at amino acid position 75 to be replaced by a cysteine (C). 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	0.14
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0088	T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.62	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.9	M;M
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.17
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.99	D;D
Vest4		0.34
MutPred		0.32		Loss of disorder (P = 0.0365);Loss of disorder (P = 0.0365);
MVP		0.51
MPC		1.0
ClinPred		0.90	D
GERP RS		4.0
Varity_R		0.34
gMVP		0.84

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: chr1-161068548;