4-74158250-G-C

Variant names:

• chr4-74158250-G-C
• rs1006120574
• NM_001144978.3:c.112G>C

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.112G>C​(p.Ala38Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,462,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: MTHFD2L NM_001144978.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13
• 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=0.10496941).

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.112G>C	p.Ala38Pro	missense	Exon 1 of 8	NP_001138450.1	Q9H903-4
	MTHFD2L	NM_001351329.2		c.112G>C	p.Ala38Pro	missense	Exon 1 of 2	NP_001338258.1
	MTHFD2L	NM_001351331.2		c.112G>C	p.Ala38Pro	missense	Exon 1 of 3	NP_001338260.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD2L	ENST00000325278.7	TSL:5 MANE Select	c.112G>C	p.Ala38Pro	missense	Exon 1 of 8	ENSP00000321984.7	Q9H903-4
	MTHFD2L	ENST00000461101.1	TSL:1	n.133G>C		non_coding_transcript_exon	Exon 1 of 2
	MTHFD2L	ENST00000429335.5	TSL:1	n.-32+14783G>C		intron	N/A	ENSP00000409391.1	Q8IY64

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152038 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000303 AC: 2 AN: 65974 AF XY: 0.0000577

Gnomad AFR exome AF: 0.000295

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000399

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 17 AN: 1310650 Hom.: 0 Cov.: 31 AF XY: 0.0000141 AC XY: 9 AN XY: 639170

African (AFR) AF: 0.0000367 AC: 1 AN: 27232

American (AMR) AF: 0.00 AC: 0 AN: 21946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19544

East Asian (EAS) AF: 0.00 AC: 0 AN: 33450

South Asian (SAS) AF: 0.00 AC: 0 AN: 65516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4534

European-Non Finnish (NFE) AF: 0.0000134 AC: 14 AN: 1041244

Other (OTH) AF: 0.0000370 AC: 2 AN: 54016

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74378

African (AFR) AF: 0.000144 AC: 6 AN: 41554

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000438 Hom.: 0

Bravo AF: 0.0000642

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	Benign	0.076
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.45	T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.090
Sift	Benign	0.049	D
Sift4G	Benign	0.19	T
Polyphen		0.59	P
Vest4		0.28
MutPred		0.22		Gain of relative solvent accessibility (P = 0.0082)
MVP		0.27
MPC		0.11
ClinPred		0.094	T
GERP RS		2.4
PromoterAI		0.018	Neutral
Varity_R		0.25
gMVP		0.39
Mutation Taster		=87/13	polymorphism

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: rs1006120574; hg19: chr4-75023967;