NM_015440.5:c.253G>A

Variant names:

• chr6-150876115-G-A
• rs758500649
• NM_015440.5:c.253G>A

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.253G>A​(p.Val85Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,606,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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: 0.0000014 (0 hom.)
• Consequence: MTHFD1L NM_015440.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16
• 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=0.11249924).

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.253G>A	p.Val85Ile	missense	Exon 2 of 28	NP_056255.2
	MTHFD1L	NM_001242767.2		c.253G>A	p.Val85Ile	missense	Exon 2 of 28	NP_001229696.1	B7ZM99
	MTHFD1L	NM_001242768.2		c.55G>A	p.Val19Ile	missense	Exon 2 of 28	NP_001229697.1	A0A087WVM4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1L	ENST00000367321.8	TSL:1 MANE Select	c.253G>A	p.Val85Ile	missense	Exon 2 of 28	ENSP00000356290.3	Q6UB35-1
	MTHFD1L	ENST00000367307.8	TSL:1	c.253G>A	p.Val85Ile	missense	Exon 2 of 8	ENSP00000356276.4	Q6UB35-2
	MTHFD1L	ENST00000611279.4	TSL:5	c.253G>A	p.Val85Ile	missense	Exon 2 of 28	ENSP00000478253.1	B7ZM99

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 245156 AF XY: 0.00000756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454678 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723182

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33156

American (AMR) AF: 0.00 AC: 0 AN: 43608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26002

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39520

South Asian (SAS) AF: 0.00 AC: 0 AN: 84332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5554

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109004

Other (OTH) AF: 0.00 AC: 0 AN: 60142

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5198

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

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

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

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	0.10
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.088
Sift	Benign	0.16	T
Sift4G	Benign	0.19	T
Polyphen		0.0010	B
Vest4		0.24
MutPred		0.44		Gain of catalytic residue at V85 (P = 0.0851)
MVP		0.34
MPC		0.13
ClinPred		0.070	T
GERP RS		4.8
Varity_R		0.036
gMVP		0.10
Mutation Taster		=85/15	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: rs758500649; hg19: chr6-151197251; COSMIC: COSV105298788;