4-74199851-G-T

Variant names:

• chr4-74199851-G-T
• rs1478006853
• NM_001144978.3:c.509G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001144978.3(MTHFD2L):​c.509G>T​(p.Gly170Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. G170E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTHFD2L NM_001144978.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.37
• Publications: 0 publications found

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]

ACMG classification

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, 0.973

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD2L	NM_001144978.3	MANE Select	c.509G>T	p.Gly170Val	missense	Exon 4 of 8	NP_001138450.1	Q9H903-4
	MTHFD2L	NM_001004346.4		c.335G>T	p.Gly112Val	missense	Exon 5 of 9	NP_001004346.2	Q9H903-1
	MTHFD2L	NM_001351310.2		c.335G>T	p.Gly112Val	missense	Exon 6 of 9	NP_001338239.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD2L	ENST00000325278.7	TSL:5 MANE Select	c.509G>T	p.Gly170Val	missense	Exon 4 of 8	ENSP00000321984.7	Q9H903-4
	MTHFD2L	ENST00000433372.5	TSL:1	n.480G>T		non_coding_transcript_exon	Exon 5 of 8
	MTHFD2L	ENST00000395759.6	TSL:5	c.509G>T	p.Gly170Val	missense	Exon 4 of 8	ENSP00000379108.2	Q9H903-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	4.9	H
PhyloP100		9.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-8.4	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.86		Loss of ubiquitination at K166 (P = 0.1322)
MVP		0.94
MPC		0.51
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.96
Mutation Taster		=10/90	disease causing

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

Other links and lift over

dbSNP: rs1478006853; hg19: chr4-75065568;