Genetic Variant ENST00000395681.6:c.1174G>A (chr22-50526142-C-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5

The ENST00000395681.6(TYMP):c.1174G>A(p.Gly392Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,485,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G392D) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TYMP
ENST00000395681.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:1

Conservation

PhyloP100: 1.29

Publications

5 publications found

Variant links:

Genes affected

TYMP (HGNC:3148): (thymidine phosphorylase) This gene encodes an angiogenic factor which promotes angiogenesis in vivo and stimulates the in vitro growth of a variety of endothelial cells. It has a highly restricted target cell specificity acting only on endothelial cells. Mutations in this gene have been associated with mitochondrial neurogastrointestinal encephalomyopathy. Multiple alternatively spliced transcript variants have been identified. [provided by RefSeq, Apr 2012]

TYMP links:

SCO2 (HGNC:10604): (synthesis of cytochrome C oxidase 2) Cytochrome c oxidase (COX) catalyzes the transfer of electrons from cytochrome c to molecular oxygen, which helps to maintain the proton gradient across the inner mitochondrial membrane that is necessary for aerobic ATP production. Human COX is a multimeric protein complex that requires several assembly factors; this gene encodes one of the COX assembly factors. The encoded protein is a metallochaperone that is involved in the biogenesis of cytochrome c oxidase subunit II. Mutations in this gene are associated with fatal infantile encephalocardiomyopathy and myopia 6. [provided by RefSeq, Oct 2014]

SCO2 Gene-Disease associations (from GenCC):

cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
myopia 6
Inheritance: AD Classification: STRONG Submitted by: G2P
autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SCO2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-50526141-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 223054.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 22-50526142-C-T is Pathogenic according to our data. Variant chr22-50526142-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 223064.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000395681.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TYMP	NM_001953.5	MANE Select	c.1160-1G>A		splice_acceptor intron	N/A	NP_001944.1
TYMP	NM_001257989.1		c.1174G>A	p.Gly392Ser	missense	Exon 9 of 10	NP_001244918.1
SCO2	NM_001169110.1		c.-155G>A		5_prime_UTR	Exon 1 of 2	NP_001162581.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TYMP	ENST00000395681.6	TSL:1	c.1174G>A	p.Gly392Ser	missense	Exon 9 of 10	ENSP00000379038.1
TYMP	ENST00000252029.8	TSL:1 MANE Select	c.1160-1G>A		splice_acceptor intron	N/A	ENSP00000252029.3
TYMP	ENST00000395678.7	TSL:1	c.1160-1G>A		splice_acceptor intron	N/A	ENSP00000379036.3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

82036

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000135

AC:

AN:

1333006

Hom.:

Cov.:

AF XY:

0.0000122

AC XY:

AN XY:

656768

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26844

American (AMR)

AF:

0.00

AC:

AN:

29370

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22808

East Asian (EAS)

AF:

0.00

AC:

AN:

30674

South Asian (SAS)

AF:

0.00

AC:

AN:

73300

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32842

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4664

European-Non Finnish (NFE)

AF:

0.0000170

AC:

AN:

1056954

Other (OTH)

AF:

0.00

AC:

AN:

55550

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

67990

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mitochondrial DNA depletion syndrome 1 (6)

Mitochondrial neurogastrointestinal encephalomyopathy (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.98

Eigen

Benign

0.18

Eigen_PC

Benign

0.069

FATHMM_MKL

Benign

0.72

M_CAP

Pathogenic

0.80

PhyloP100

1.3

ClinPred

1.0

GERP RS

3.2

PromoterAI

0.021

Neutral

(source)

Mutation Taster

=11/89

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.92

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.26

Position offset: -2

DS_AL_spliceai

0.92

Position offset: -1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over