22-50548464-A-T

Position:

• chr22-50548464-A-T

Variant summary

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

The NM_138433.5(KLHDC7B):​c.2221A>T​(p.Met741Leu) 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. 16/20 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)
• Consequence: KLHDC7B NM_138433.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.06

Genes affected

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

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=0.048706174).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHDC7B	NM_138433.5	c.2221A>T	p.Met741Leu	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.2221A>T	p.Met741Leu	missense_variant	1/1		NM_138433.5	ENSP00000497256	P3
KLHDC7B	ENST00000395676.4	c.298A>T	p.Met100Leu	missense_variant	1/1			ENSP00000379034	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

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

Jun 18, 2021

The c.298A>T (p.M100L) alteration is located in exon 1 (coding exon 1) of the KLHDC7B gene. This alteration results from a A to T substitution at nucleotide position 298, causing the methionine (M) at amino acid position 100 to be replaced by a leucine (L). 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	0.088
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.017
DANN	Benign	0.40
DEOGEN2	Benign	0.0017	.;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.26	T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	.;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.070	.;N
REVEL	Benign	0.16
Sift	Benign	0.27	.;T
Sift4G	Benign	0.67	.;T
Polyphen		0.0	.;B
Vest4		0.068
MutPred		0.18		.;Loss of methylation at R102 (P = 0.2028);
MVP		0.69
ClinPred		0.093	T
GERP RS		-7.6
Varity_R		0.082
gMVP		0.070

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: chr22-50986893;