Genetic Variant NM_004795.4:c.43_45delCCG (chr13-33016472-GGCC-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_004795.4(KL):c.43_45delCCG(p.Pro15del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000764 in 916,514 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

KL
NM_004795.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.487

Publications

0 publications found

Variant links:

Genes affected

KL (HGNC:6344): (klotho) This gene encodes a type-I membrane protein that is related to beta-glucosidases. Reduced production of this protein has been observed in patients with chronic renal failure (CRF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. Also, mutations within this protein have been associated with ageing and bone loss. [provided by RefSeq, Jul 2008]

KL Gene-Disease associations (from GenCC):

tumoral calcinosis, hyperphosphatemic, familial, 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
tumoral calcinosis, hyperphosphatemic, familial, 3
Inheritance: AR, Unknown Classification: LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

KL links:

ENSG00000308044 (HGNC:):

ENSG00000308044 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_004795.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4 link	c.43_45delCCG	p.Pro15del	conservative_inframe_deletion	Exon 1 of 5	ENST00000380099.4	NP_004786.2	Q9UEF7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KL	ENST00000380099.4 link	c.43_45delCCG	p.Pro15del	conservative_inframe_deletion	Exon 1 of 5	1	NM_004795.4	ENSP00000369442.3	Q9UEF7-1
KL	ENST00000487852.1 link	n.51_53delCCG		non_coding_transcript_exon_variant	Exon 1 of 5	5
ENSG00000308044	ENST00000830674.1 link	n.-231_-229delGGC		upstream_gene_variant
ENSG00000308044	ENST00000830675.1 link	n.-246_-244delGGC		upstream_gene_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

160

AF XY:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000764

AC:

AN:

916514

Hom.:

AF XY:

0.00000932

AC XY:

AN XY:

429166

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000560

AC:

AN:

17864

American (AMR)

AF:

0.000881

AC:

AN:

3404

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7744

East Asian (EAS)

AF:

0.0000969

AC:

AN:

10320

South Asian (SAS)

AF:

0.0000553

AC:

AN:

18078

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8762

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2082

European-Non Finnish (NFE)

AF:

0.00000123

AC:

AN:

815802

Other (OTH)

AF:

0.00

AC:

AN:

32458

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000443358), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.49

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over