Genetic Variant CDC37L1:p.Leu243Phe (chr9-4697861-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_017913.4(CDC37L1):c.729A>T(p.Leu243Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,960 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CDC37L1
NM_017913.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.698

Variant links:

Genes affected

CDC37L1 (HGNC:17179): (cell division cycle 37 like 1, HSP90 cochaperone) CDC37L1 is a cytoplasmic phosphoprotein that exists in complex with HSP90 (HSPCA; MIM 140571) as well as several other proteins involved in HSP90-mediated protein folding (Scholz et al., 2001 [PubMed 11413142]).[supplied by OMIM, Mar 2008]

CDC37L1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDC37L1	NM_017913.4 link	c.729A>T	p.Leu243Phe	missense_variant	Exon 5 of 7	ENST00000381854.4	NP_060383.2	Q7L3B6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC37L1	ENST00000381854.4 link	c.729A>T	p.Leu243Phe	missense_variant	Exon 5 of 7	1	NM_017913.4	ENSP00000371278.3		Q7L3B6
CDC37L1	ENST00000381858.5 link	c.729A>T	p.Leu243Phe	missense_variant	Exon 5 of 7	5		ENSP00000371282.1		B1AL69

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250840

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135606

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000656

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460960

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726794

show subpopulations

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.729A>T (p.L243F) alteration is located in exon 6 (coding exon 5) of the CDC37L1 gene. This alteration results from a A to T substitution at nucleotide position 729, causing the leucine (L) at amino acid position 243 to be replaced by a phenylalanine (F). 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

0.21

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

.;T

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.43

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.2

.;M

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.27

Sift

Benign

0.085

T;T

Sift4G

Benign

0.11

T;T

Polyphen

1.0

.;D

Vest4

0.42

MutPred

0.37

Loss of stability (P = 0.0543);Loss of stability (P = 0.0543);

MVP

0.25

MPC

0.63

ClinPred

0.66

GERP RS

2.8

Varity_R

0.031

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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