22-50548665-G-A

Position:

• chr22-50548665-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138433.5(KLHDC7B):​c.2422G>A​(p.Gly808Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000219 in 1,368,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: KLHDC7B NM_138433.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51

Genes affected

KLHDC7B (HGNC:25145): (kelch domain containing 7B)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18765062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHDC7B	NM_138433.5	c.2422G>A	p.Gly808Ser	missense_variant	1/1	ENST00000648057.3	NP_612442.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHDC7B	ENST00000648057.3	c.2422G>A	p.Gly808Ser	missense_variant	1/1		NM_138433.5	ENSP00000497256.1
KLHDC7B	ENST00000395676.4	c.499G>A	p.Gly167Ser	missense_variant	1/1	6		ENSP00000379034.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000219 AC: 3 AN: 1368138 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 673020

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: 0.00000281

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Dec 15, 2023

The c.499G>A (p.G167S) alteration is located in exon 1 (coding exon 1) of the KLHDC7B gene. This alteration results from a G to A substitution at nucleotide position 499, causing the glycine (G) at amino acid position 167 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	0.091
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.0084	.;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.36	T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.5	.;L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.91	.;N
REVEL	Benign	0.18
Sift	Benign	0.14	.;T
Sift4G	Uncertain	0.050	.;T
Polyphen		0.98	.;D
Vest4		0.14
MutPred		0.25		.;Gain of phosphorylation at G167 (P = 0.0054);
MVP		0.72
ClinPred		0.25	T
GERP RS		3.1
Varity_R		0.060
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: chr22-50987094;