9-4701906-G-A

Variant names:

• chr9-4701906-G-A
• rs1841401387
• NM_017913.4:c.790G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017913.4(CDC37L1):​c.790G>A​(p.Glu264Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,436 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E264Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDC37L1 NM_017913.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.86
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017913.4. 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
	CDC37L1	NM_017913.4	MANE Select	c.790G>A	p.Glu264Lys	missense	Exon 6 of 7	NP_060383.2	Q7L3B6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDC37L1	ENST00000381854.4	TSL:1 MANE Select	c.790G>A	p.Glu264Lys	missense	Exon 6 of 7	ENSP00000371278.3	Q7L3B6
	CDC37L1	ENST00000906225.1		c.730G>A	p.Glu244Lys	missense	Exon 6 of 7	ENSP00000576284.1
	CDC37L1	ENST00000381858.5	TSL:5	c.790G>A	p.Glu264Lys	missense	Exon 6 of 7	ENSP00000371282.1	B1AL69

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452436 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722620

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

African (AFR) AF: 0.00 AC: 0 AN: 32940

American (AMR) AF: 0.00 AC: 0 AN: 43124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25908

East Asian (EAS) AF: 0.00 AC: 0 AN: 39420

South Asian (SAS) AF: 0.00 AC: 0 AN: 84556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108340

Other (OTH) AF: 0.00 AC: 0 AN: 59984

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.38
Sift	Benign	0.064	T
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.56		Gain of MoRF binding (P = 0.0049)
MVP		0.26
MPC		0.64
ClinPred		0.87	D
GERP RS		6.2
Varity_R		0.55
gMVP		0.33
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1841401387; hg19: chr9-4701906;