Genetic Variant NM_001071.4:c.205+200C>A (chr18-658147-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_001071.4(TYMS):c.205+200C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00994 in 1,583,902 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0079 ( 4 hom., cov: 33)

Exomes 𝑓: 0.010 ( 88 hom. )

Consequence

TYMS
NM_001071.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.722

Publications

6 publications found

Variant links:

Genes affected

TYMS (HGNC:12441): (thymidylate synthetase) Thymidylate synthase catalyzes the methylation of deoxyuridylate to deoxythymidylate using, 10-methylenetetrahydrofolate (methylene-THF) as a cofactor. This function maintains the dTMP (thymidine-5-prime monophosphate) pool critical for DNA replication and repair. The enzyme has been of interest as a target for cancer chemotherapeutic agents. It is considered to be the primary site of action for 5-fluorouracil, 5-fluoro-2-prime-deoxyuridine, and some folate analogs. Expression of this gene and that of a naturally occurring antisense transcript, mitochondrial enolase superfamily member 1 (GeneID:55556), vary inversely when cell-growth progresses from late-log to plateau phase. Polymorphisms in this gene may be associated with etiology of neoplasia, including breast cancer, and response to chemotherapy. [provided by RefSeq, Aug 2017]

TYMS links:

TYMSOS (HGNC:29553): (TYMS opposite strand RNA)

TYMSOS links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.095).

BP6

Variant 18-658147-C-A is Benign according to our data. Variant chr18-658147-C-A is described in ClinVar as Benign. ClinVar VariationId is 2648512.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 4 Digenic gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001071.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TYMS	NM_001071.4	MANE Select	c.205+200C>A	intron	N/A	NP_001062.1	Q53Y97
TYMS	NM_001354867.2		c.205+200C>A	intron	N/A	NP_001341796.1	P04818-2
TYMS	NM_001354868.2		c.205+200C>A	intron	N/A	NP_001341797.1	P04818-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TYMS	ENST00000323274.15	TSL:1 MANE Select	c.205+200C>A	intron	N/A	ENSP00000315644.10	P04818-1
TYMS	ENST00000323224.7	TSL:1	c.205+200C>A	intron	N/A	ENSP00000314727.7	P04818-2
TYMS	ENST00000323250.9	TSL:1	c.205+200C>A	intron	N/A	ENSP00000314902.5	P04818-3

Frequencies

GnomAD3 genomes

AF:

0.00787

AC:

1196

AN:

151932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00225

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.00968

Gnomad NFE

AF:

0.0115

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00751

AC:

1546

AN:

205736

AF XY:

0.00748

show subpopulations

Gnomad AFR exome

AF:

0.00195

Gnomad AMR exome

AF:

0.00787

Gnomad ASJ exome

AF:

0.0184

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00161

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.0102

AC:

14546

AN:

1431848

Hom.:

Cov.:

AF XY:

0.0100

AC XY:

7126

AN XY:

711104

show subpopulations

African (AFR)

AF:

0.00186

AC:

AN:

32810

American (AMR)

AF:

0.00810

AC:

342

AN:

42242

Ashkenazi Jewish (ASJ)

AF:

0.0176

AC:

450

AN:

25562

East Asian (EAS)

AF:

0.0000262

AC:

AN:

38194

South Asian (SAS)

AF:

0.00241

AC:

199

AN:

82650

European-Finnish (FIN)

AF:

0.00249

AC:

113

AN:

45442

Middle Eastern (MID)

AF:

0.0128

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.0116

AC:

12726

AN:

1100094

Other (OTH)

AF:

0.00983

AC:

581

AN:

59132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

827

1654

2482

3309

4136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

468

936

1404

1872

2340

<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:

0.00786

AC:

1195

AN:

152054

Hom.:

Cov.:

AF XY:

0.00749

AC XY:

557

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

41466

American (AMR)

AF:

0.0120

AC:

184

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00270

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00217

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0115

AC:

781

AN:

67954

Other (OTH)

AF:

0.0118

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

119

178

238

297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.0108

Hom.:

Bravo

AF:

0.00818

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

3.7

(source)

DANN

Benign

0.68

PhyloP100

-0.72

PromoterAI

0.066

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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