6-150866025-C-T

Variant names:

• chr6-150866025-C-T
• rs1053900238
• NM_015440.5:c.203C>T

Variant summary

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

The NM_015440.5(MTHFD1L):​c.203C>T​(p.Pro68Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,407,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P68H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: MTHFD1L NM_015440.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.310
• Publications: 0 publications found

Genes affected

MTHFD1L (HGNC:21055): (methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1 like) The protein encoded by this gene is involved in the synthesis of tetrahydrofolate (THF) in the mitochondrion. THF is important in the de novo synthesis of purines and thymidylate and in the regeneration of methionine from homocysteine. Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jun 2011]

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=0.08150005).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015440.5. 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
	MTHFD1L	NM_015440.5	MANE Select	c.203C>T	p.Pro68Leu	missense	Exon 1 of 28	NP_056255.2
	MTHFD1L	NM_001242767.2		c.203C>T	p.Pro68Leu	missense	Exon 1 of 28	NP_001229696.1	B7ZM99
	MTHFD1L	NM_001350488.3		c.203C>T	p.Pro68Leu	missense	Exon 1 of 8	NP_001337417.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1L	ENST00000367321.8	TSL:1 MANE Select	c.203C>T	p.Pro68Leu	missense	Exon 1 of 28	ENSP00000356290.3	Q6UB35-1
	MTHFD1L	ENST00000367307.8	TSL:1	c.203C>T	p.Pro68Leu	missense	Exon 1 of 8	ENSP00000356276.4	Q6UB35-2
	MTHFD1L	ENST00000611279.4	TSL:5	c.203C>T	p.Pro68Leu	missense	Exon 1 of 28	ENSP00000478253.1	B7ZM99

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152016 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome AF: 0.0000104 AC: 13 AN: 1255068 Hom.: 0 Cov.: 32 AF XY: 0.0000114 AC XY: 7 AN XY: 615980

African (AFR) AF: 0.00 AC: 0 AN: 25098

American (AMR) AF: 0.00 AC: 0 AN: 17322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20172

East Asian (EAS) AF: 0.00 AC: 0 AN: 27344

South Asian (SAS) AF: 0.00 AC: 0 AN: 61654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3632

European-Non Finnish (NFE) AF: 0.0000118 AC: 12 AN: 1017748

Other (OTH) AF: 0.0000194 AC: 1 AN: 51440

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152016 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74258

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67946

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

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	0.087
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.0085	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.31
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.86	N
REVEL	Benign	0.011
Sift	Benign	0.23	T
Sift4G	Benign	0.45	T
Polyphen		0.020	B
Vest4		0.15
MutPred		0.33		Loss of glycosylation at P68 (P = 0.0348)
MVP		0.092
MPC		0.16
ClinPred		0.072	T
GERP RS		1.5
PromoterAI		-0.0059	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.15
Mutation Taster		=92/8	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: rs1053900238; hg19: chr6-151187161;