NM_017913.4:c.824A>C

Variant names:

• chr9-4701940-A-C
• rs753838718
• NM_017913.4:c.824A>C

Variant summary

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

The NM_017913.4(CDC37L1):​c.824A>C​(p.Gln275Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,104 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. Q275L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDC37L1 NM_017913.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.13
• 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.824A>C	p.Gln275Pro	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.824A>C	p.Gln275Pro	missense	Exon 6 of 7	ENSP00000371278.3	Q7L3B6
	CDC37L1	ENST00000906225.1		c.764A>C	p.Gln255Pro	missense	Exon 6 of 7	ENSP00000576284.1
	CDC37L1	ENST00000381858.5	TSL:5	c.824A>C	p.Gln275Pro	missense	Exon 6 of 7	ENSP00000371282.1	B1AL69

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000425 AC: 1 AN: 235322 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000921

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000278 AC: 4 AN: 1439942 Hom.: 0 Cov.: 29 AF XY: 0.00000279 AC XY: 2 AN XY: 716596

⚠️ 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: 32156

American (AMR) AF: 0.00 AC: 0 AN: 40982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25582

East Asian (EAS) AF: 0.00 AC: 0 AN: 39178

South Asian (SAS) AF: 0.00 AC: 0 AN: 83154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52830

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.00000363 AC: 4 AN: 1100964

Other (OTH) AF: 0.00 AC: 0 AN: 59446

⚠️ 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 AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74302

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.16
Sift	Uncertain	0.015	D
Sift4G	Benign	0.26	T
Polyphen		0.092	B
Vest4		0.56
MutPred		0.69		Loss of MoRF binding (P = 0.0583)
MVP		0.38
MPC		0.35
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.40
gMVP		0.44
Mutation Taster		=52/48	polymorphism

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: rs753838718; hg19: chr9-4701940;