chr13-33016472-GGCC-G

Variant names:

• chr13-33016472-GGCC-G
• rs1050352800
• NM_004795.4:c.43_45delCCG

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.487
• Publications: 0 publications found

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: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

LOC124903151 (HGNC:):

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004795.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KL	NM_004795.4	MANE Select	c.43_45delCCG	p.Pro15del	conservative_inframe_deletion	Exon 1 of 5	NP_004786.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KL	ENST00000380099.4	TSL:1 MANE Select	c.43_45delCCG	p.Pro15del	conservative_inframe_deletion	Exon 1 of 5	ENSP00000369442.3	Q9UEF7-1
	KL	ENST00000487852.1	TSL:5	n.51_53delCCG		non_coding_transcript_exon	Exon 1 of 5
	ENSG00000308044	ENST00000830674.1		n.-231_-229delGGC		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00 AC: 0 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: 7 AN: 916514 Hom.: 0 AF XY: 0.00000932 AC XY: 4 AN XY: 429166

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

African (AFR) AF: 0.0000560 AC: 1 AN: 17864

American (AMR) AF: 0.000881 AC: 3 AN: 3404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7744

East Asian (EAS) AF: 0.0000969 AC: 1 AN: 10320

South Asian (SAS) AF: 0.0000553 AC: 1 AN: 18078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2082

European-Non Finnish (NFE) AF: 0.00000123 AC: 1 AN: 815802

Other (OTH) AF: 0.00 AC: 0 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.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

Other links and lift over

dbSNP: rs1050352800; hg19: chr13-33590610;