Genetic Variant MTHFD2L:p.Gly170Glu (chr4-74199851-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001144978.3(MTHFD2L):c.509G>A(p.Gly170Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,502 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MTHFD2L
NM_001144978.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.37

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:

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ACMG classification

Classification was made for transcript

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, 0.961

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.509G>A	p.Gly170Glu	missense	Exon 4 of 8	NP_001138450.1	Q9H903-4
MTHFD2L	NM_001004346.4		c.335G>A	p.Gly112Glu	missense	Exon 5 of 9	NP_001004346.2	Q9H903-1
MTHFD2L	NM_001351310.2		c.335G>A	p.Gly112Glu	missense	Exon 6 of 9	NP_001338239.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTHFD2L	ENST00000325278.7	TSL:5 MANE Select	c.509G>A	p.Gly170Glu	missense	Exon 4 of 8	ENSP00000321984.7	Q9H903-4
MTHFD2L	ENST00000433372.5	TSL:1	n.480G>A		non_coding_transcript_exon	Exon 5 of 8
MTHFD2L	ENST00000395759.6	TSL:5	c.509G>A	p.Gly170Glu	missense	Exon 4 of 8	ENSP00000379108.2	Q9H903-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461502

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727060

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111752

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

4.9

PhyloP100

9.4

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-7.3

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

0.83

Gain of solvent accessibility (P = 0.012)

MVP

0.93

MPC

0.52

ClinPred

1.0

GERP RS

5.2

Varity_R

0.97

gMVP

0.98

Mutation Taster

=6/94

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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