NM_001144978.3:c.34C>T

Variant names:

• chr4-74158172-C-T
• rs1724552920
• NM_001144978.3:c.34C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001144978.3(MTHFD2L):​c.34C>T​(p.Arg12Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000131 in 1,528,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: MTHFD2L NM_001144978.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.215
• 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]

ENSG00000269559 (HGNC:):

ACMG classification

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=0.17183712).

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.34C>T	p.Arg12Cys	missense	Exon 1 of 8	NP_001138450.1	Q9H903-4
	MTHFD2L	NM_001004346.4		c.-175C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_001004346.2	Q9H903-1
	MTHFD2L	NM_001351314.2		c.-562C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001338243.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD2L	ENST00000325278.7	TSL:5 MANE Select	c.34C>T	p.Arg12Cys	missense	Exon 1 of 8	ENSP00000321984.7	Q9H903-4
	MTHFD2L	ENST00000461101.1	TSL:1	n.55C>T		non_coding_transcript_exon	Exon 1 of 2
	MTHFD2L	ENST00000429335.5	TSL:1	n.-32+14705C>T		intron	N/A	ENSP00000409391.1	Q8IY64

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1376424 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 677722

African (AFR) AF: 0.00 AC: 0 AN: 31118

American (AMR) AF: 0.0000297 AC: 1 AN: 33644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23902

East Asian (EAS) AF: 0.00 AC: 0 AN: 35464

South Asian (SAS) AF: 0.00 AC: 0 AN: 76524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5296

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1070938

Other (OTH) AF: 0.00 AC: 0 AN: 57120

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.21
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.084
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.039	D
Polyphen		0.91	P
Vest4		0.22
MutPred		0.48		Loss of methylation at R12 (P = 0.0127)
MVP		0.31
MPC		0.47
ClinPred		0.56	D
GERP RS		-1.3
PromoterAI		0.0052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.11
gMVP		0.30
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1724552920; hg19: chr4-75023889;