Genetic Variant NM_004795.4:c.820-46C>G (chr13-33053721-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004795.4(KL):c.820-46C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,580,028 control chromosomes in the GnomAD database, including 20,050 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 1942 hom., cov: 32)

Exomes 𝑓: 0.15 ( 18108 hom. )

Consequence

KL
NM_004795.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.323

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 13-33053721-C-G is Benign according to our data. Variant chr13-33053721-C-G is described in ClinVar as [Benign]. Clinvar id is 1181821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
KL	NM_004795.4 link	c.820-46C>G	intron_variant	Intron 1 of 4	ENST00000380099.4	NP_004786.2	Q9UEF7-1
KL	XM_006719895.3 link	c.-102-46C>G	intron_variant	Intron 1 of 4		XP_006719958.1
KL	XM_047430775.1 link	c.820-46C>G	intron_variant	Intron 1 of 3		XP_047286731.1
KL	XM_047430776.1 link	c.820-46C>G	intron_variant	Intron 1 of 3		XP_047286732.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KL	ENST00000380099.4 link	c.820-46C>G		intron_variant	Intron 1 of 4	1	NM_004795.4	ENSP00000369442.3		Q9UEF7-1
KL	ENST00000487852.1 link	n.828-46C>G		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.156

AC:

23701

AN:

152056

Hom.:

1941

Cov.:

show subpopulations

Gnomad AFR

AF:

0.183

Gnomad AMI

AF:

0.106

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.216

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.160

Gnomad FIN

AF:

0.193

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.155

Gnomad OTH

AF:

0.149

GnomAD3 exomes

AF:

0.141

AC:

35039

AN:

248784

Hom.:

2909

AF XY:

0.146

AC XY:

19691

AN XY:

134806

show subpopulations

Gnomad AFR exome

AF:

0.181

Gnomad AMR exome

AF:

0.0734

Gnomad ASJ exome

AF:

0.206

Gnomad EAS exome

AF:

0.00114

Gnomad SAS exome

AF:

0.176

Gnomad FIN exome

AF:

0.200

Gnomad NFE exome

AF:

0.152

Gnomad OTH exome

AF:

0.147

GnomAD4 exome

AF:

0.154

AC:

220192

AN:

1427854

Hom.:

18108

Cov.:

AF XY:

0.155

AC XY:

110347

AN XY:

712302

show subpopulations

Gnomad4 AFR exome

AF:

0.178

Gnomad4 AMR exome

AF:

0.0768

Gnomad4 ASJ exome

AF:

0.209

Gnomad4 EAS exome

AF:

0.000861

Gnomad4 SAS exome

AF:

0.174

Gnomad4 FIN exome

AF:

0.198

Gnomad4 NFE exome

AF:

0.157

Gnomad4 OTH exome

AF:

0.165

GnomAD4 genome

AF:

0.156

AC:

23714

AN:

152174

Hom.:

1942

Cov.:

AF XY:

0.157

AC XY:

11677

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.183

Gnomad4 AMR

AF:

0.103

Gnomad4 ASJ

AF:

0.216

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.162

Gnomad4 FIN

AF:

0.193

Gnomad4 NFE

AF:

0.155

Gnomad4 OTH

AF:

0.147

Alfa

AF:

0.107

Hom.:

237

Bravo

AF:

0.148

Asia WGS

AF:

0.0750

AC:

264

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.92

DANN

Benign

0.41

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over