11-90218147-G-T

Variant names:

• chr11-90218147-G-T
• rs146907011
• NM_012124.3:c.102C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_012124.3(CHORDC1):​c.102C>A​(p.His34Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,422,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CHORDC1 NM_012124.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.32
• Publications: 2 publications found

Genes affected

CHORDC1 (HGNC:14525): (cysteine and histidine rich domain containing 1) Enables Hsp90 protein binding activity. Predicted to be involved in centrosome duplication; chaperone-mediated protein folding; and regulation of cellular response to heat. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012124.3. 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
	CHORDC1	NM_012124.3	MANE Select	c.102C>A	p.His34Gln	missense	Exon 2 of 11	NP_036256.2	Q9UHD1-1
	CHORDC1	NM_001144073.2		c.102C>A	p.His34Gln	missense	Exon 2 of 10	NP_001137545.1	Q9UHD1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHORDC1	ENST00000320585.11	TSL:1 MANE Select	c.102C>A	p.His34Gln	missense	Exon 2 of 11	ENSP00000319255.6	Q9UHD1-1
	CHORDC1	ENST00000457199.6	TSL:1	c.102C>A	p.His34Gln	missense	Exon 2 of 10	ENSP00000401080.2	Q9UHD1-2
	CHORDC1	ENST00000907759.1		c.102C>A	p.His34Gln	missense	Exon 2 of 10	ENSP00000577818.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000470 AC: 1 AN: 212912 AF XY: 0.00000864

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422430 Hom.: 0 Cov.: 28 AF XY: 0.00000141 AC XY: 1 AN XY: 707146

⚠️ 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: 30356

American (AMR) AF: 0.00 AC: 0 AN: 35044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24870

East Asian (EAS) AF: 0.00 AC: 0 AN: 38068

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52944

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5602

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098048

Other (OTH) AF: 0.00 AC: 0 AN: 58696

⚠️ 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.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	0.023
Eigen_PC	Benign	-0.094
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.085	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		2.3
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.94		Gain of helix (P = 0.0696)
MVP		0.79
MPC		0.59
ClinPred		0.97	D
GERP RS		2.9
Varity_R		0.84
gMVP		0.79
Mutation Taster		=9/91	disease causing

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

Other links and lift over

dbSNP: rs146907011; hg19: chr11-89951315;