4-74158199-T-A

Variant names:

• chr4-74158199-T-A
• rs1724569634
• NM_001144978.3:c.61T>A

Variant summary

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

The NM_001004346.4(MTHFD2L):​c.-148T>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,525,560 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: 0.000014 (0 hom.)
• Consequence: MTHFD2L NM_001004346.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.30
• 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=0.13025185).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004346.4. 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.61T>A	p.Leu21Met	missense	Exon 1 of 8	NP_001138450.1	Q9H903-4
	MTHFD2L	NM_001004346.4		c.-148T>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_001004346.2	Q9H903-1
	MTHFD2L	NM_001351314.2		c.-535T>A		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.61T>A	p.Leu21Met	missense	Exon 1 of 8	ENSP00000321984.7	Q9H903-4
	MTHFD2L	ENST00000461101.1	TSL:1	n.82T>A		non_coding_transcript_exon	Exon 1 of 2
	MTHFD2L	ENST00000429335.5	TSL:1	n.-32+14732T>A		intron	N/A	ENSP00000409391.1	Q8IY64

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152066 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000138 AC: 19 AN: 1373494 Hom.: 0 Cov.: 31 AF XY: 0.0000148 AC XY: 10 AN XY: 675790

African (AFR) AF: 0.00 AC: 0 AN: 30912

American (AMR) AF: 0.00 AC: 0 AN: 32760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23536

East Asian (EAS) AF: 0.00 AC: 0 AN: 35452

South Asian (SAS) AF: 0.00 AC: 0 AN: 75462

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5252

European-Non Finnish (NFE) AF: 0.0000178 AC: 19 AN: 1068896

Other (OTH) AF: 0.00 AC: 0 AN: 56906

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152066 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74274

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

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	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0041	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.037
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.054	T
Polyphen		0.53	P
Vest4		0.21
MutPred		0.27		Gain of catalytic residue at L21 (P = 0.024)
MVP		0.34
MPC		0.39
ClinPred		0.29	T
GERP RS		-0.96
PromoterAI		0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.086
gMVP		0.12
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1724569634; hg19: chr4-75023916;