dbSNP rs1724552920: MTHFD2L:p.Arg12Ser (chr4-74158172-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001144978.3(MTHFD2L):c.34C>A(p.Arg12Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,376,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. R12C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

MTHFD2L
NM_001144978.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.215

Publications

0 publications found

Variant links:

Genes affected

MTHFD2L (HGNC:31865): (methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2 like) Predicted to enable methenyltetrahydrofolate cyclohydrolase activity; methylenetetrahydrofolate dehydrogenase (NAD+) activity; and methylenetetrahydrofolate dehydrogenase (NADP+) activity. Predicted to be involved in tetrahydrofolate interconversion. Predicted to be located in mitochondrial matrix. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

MTHFD2L links:

ENSG00000269559 (HGNC:):

ENSG00000269559 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06804171).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144978.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTHFD2L	NM_001144978.3	MANE Select	c.34C>A	p.Arg12Ser	missense	Exon 1 of 8	NP_001138450.1	Q9H903-4
MTHFD2L	NM_001351329.2		c.34C>A	p.Arg12Ser	missense	Exon 1 of 2	NP_001338258.1
MTHFD2L	NM_001351331.2		c.34C>A	p.Arg12Ser	missense	Exon 1 of 3	NP_001338260.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTHFD2L	ENST00000325278.7	TSL:5 MANE Select	c.34C>A	p.Arg12Ser	missense	Exon 1 of 8	ENSP00000321984.7	Q9H903-4
MTHFD2L	ENST00000461101.1	TSL:1	n.55C>A		non_coding_transcript_exon	Exon 1 of 2
MTHFD2L	ENST00000429335.5	TSL:1	n.-32+14705C>A		intron	N/A	ENSP00000409391.1	Q8IY64

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.27e-7

AC:

AN:

1376424

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

677722

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31118

American (AMR)

AF:

0.00

AC:

AN:

33644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23902

East Asian (EAS)

AF:

0.00

AC:

AN:

35464

South Asian (SAS)

AF:

0.00

AC:

AN:

76524

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5296

European-Non Finnish (NFE)

AF:

9.34e-7

AC:

AN:

1070938

Other (OTH)

AF:

0.00

AC:

AN:

57120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0092

LIST_S2

Benign

0.55

M_CAP

Benign

0.064

MetaRNN

Benign

0.068

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.21

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.40

REVEL

Benign

0.018

Sift

Benign

0.25

Sift4G

Benign

0.89

Polyphen

0.0010

Vest4

0.24

MutPred

0.33

Loss of methylation at R12 (P = 0.0127)

MVP

0.085

MPC

0.33

ClinPred

0.37

GERP RS

-1.3

PromoterAI

-0.071

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.068

gMVP

0.35

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over