10-75044017-C-G

Variant names:

• chr10-75044017-C-G
• rs574016736
• NM_001003892.3:c.201G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001003892.3(DUSP29):​c.201G>C​(p.Glu67Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E67K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DUSP29 NM_001003892.3 missense, splice_region
• Scores: Splicing: ADA: 0.9717
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92
• Publications: 0 publications found

Genes affected

DUSP29 (HGNC:23481): (dual specificity phosphatase 29) Enables protein homodimerization activity and protein tyrosine/serine/threonine phosphatase activity. Involved in protein dephosphorylation. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000285810 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001003892.3. 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
	DUSP29	NM_001003892.3	MANE Select	c.201G>C	p.Glu67Asp	missense splice_region	Exon 3 of 4	NP_001003892.1	Q68J44
	DUSP29	NM_001384909.1		c.201G>C	p.Glu67Asp	missense splice_region	Exon 4 of 5	NP_001371838.1	Q68J44

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUSP29	ENST00000338487.6	TSL:1 MANE Select	c.201G>C	p.Glu67Asp	missense splice_region	Exon 3 of 4	ENSP00000340609.5	Q68J44
	DUSP29	ENST00000944289.1		c.201G>C	p.Glu67Asp	missense splice_region	Exon 4 of 5	ENSP00000614348.1
	ENSG00000285810	ENST00000649504.1		n.91+2051C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455742 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 723822

⚠️ 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: 33360

American (AMR) AF: 0.00 AC: 0 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 86100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4214

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110034

Other (OTH) AF: 0.00 AC: 0 AN: 60102

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.66
Sift	Benign	0.20	T
Sift4G	Benign	0.43	T
Polyphen		1.0	D
Vest4		0.73
MutPred		0.55		Loss of sheet (P = 0.0126)
MVP		0.63
MPC		0.89
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.57
gMVP		0.73
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs574016736; hg19: chr10-76803775;