9-4685157-A-G

Variant names:

• chr9-4685157-A-G
• NM_017913.4:c.413A>G

Variant summary

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

The NM_017913.4(CDC37L1):​c.413A>G​(p.Lys138Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,458,462 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDC37L1 NM_017913.4 missense, splice_region
• Scores: Splicing: ADA: 0.9986
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.79

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]

ACMG classification

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	c.413A>G	p.Lys138Arg	missense_variant, splice_region_variant	Exon 2 of 7	ENST00000381854.4	NP_060383.2
CDC37L1	XM_047423583.1	c.413A>G	p.Lys138Arg	missense_variant, splice_region_variant	Exon 2 of 4		XP_047279539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDC37L1	ENST00000381854.4	c.413A>G	p.Lys138Arg	missense_variant, splice_region_variant	Exon 2 of 7	1	NM_017913.4	ENSP00000371278.3
CDC37L1	ENST00000381858.5	c.413A>G	p.Lys138Arg	missense_variant, splice_region_variant	Exon 2 of 7	5		ENSP00000371282.1
CDC37L1	ENST00000479095.1	n.466A>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458462 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725686

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.413A>G (p.K138R) alteration is located in exon 3 (coding exon 2) of the CDC37L1 gene. This alteration results from a A to G substitution at nucleotide position 413, causing the lysine (K) at amino acid position 138 to be replaced by an arginine (R). 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	0.12
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.5	.;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.22
Sift	Benign	0.049	D;D
Sift4G	Benign	0.062	T;T
Polyphen		0.99	.;D
Vest4		0.80
MutPred		0.14		Loss of methylation at K138 (P = 0.0056);Loss of methylation at K138 (P = 0.0056);
MVP		0.42
MPC		0.55
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.37
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.070		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: chr9-4685157;