6-151015603-C-G

Variant names:

• chr6-151015603-C-G
• rs509474
• NM_015440.5:c.2496C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001242767.2(MTHFD1L):​c.2499C>G​(p.Ser833Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 1,613,736 control chromosomes in the GnomAD database, including 171,821 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.54 (24604 hom., cov: 32)
  • Exomes 𝑓: 0.44 (147217 hom.)
• Consequence: MTHFD1L NM_001242767.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.53
• Publications: 18 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP7: Synonymous conserved (PhyloP=-4.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242767.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1L	NM_015440.5	MANE Select	c.2496C>G	p.Ser832Ser	synonymous	Exon 24 of 28	NP_056255.2
	MTHFD1L	NM_001242767.2		c.2499C>G	p.Ser833Ser	synonymous	Exon 24 of 28	NP_001229696.1
	MTHFD1L	NM_001242768.2		c.2301C>G	p.Ser767Ser	synonymous	Exon 24 of 28	NP_001229697.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1L	ENST00000367321.8	TSL:1 MANE Select	c.2496C>G	p.Ser832Ser	synonymous	Exon 24 of 28	ENSP00000356290.3
	MTHFD1L	ENST00000611279.4	TSL:5	c.2499C>G	p.Ser833Ser	synonymous	Exon 24 of 28	ENSP00000478253.1
	MTHFD1L	ENST00000939695.1		c.2490C>G	p.Ser830Ser	synonymous	Exon 24 of 28	ENSP00000609754.1

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82165 AN: 151882 Hom.: 24551 Cov.: 32

Gnomad AFR AF: 0.804

Gnomad AMI AF: 0.460

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.675

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.535

GnomAD2 exomes AF: 0.451 AC: 113470 AN: 251344 AF XY: 0.445

Gnomad AFR exome AF: 0.810

Gnomad AMR exome AF: 0.339

Gnomad ASJ exome AF: 0.512

Gnomad EAS exome AF: 0.675

Gnomad FIN exome AF: 0.365

Gnomad NFE exome AF: 0.441

Gnomad OTH exome AF: 0.453

GnomAD4 exome AF: 0.441 AC: 644691 AN: 1461736 Hom.: 147217 Cov.: 52 AF XY: 0.437 AC XY: 318041 AN XY: 727174

African (AFR) AF: 0.821 AC: 27485 AN: 33478

American (AMR) AF: 0.352 AC: 15731 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 13386 AN: 26128

East Asian (EAS) AF: 0.655 AC: 25990 AN: 39696

South Asian (SAS) AF: 0.336 AC: 28948 AN: 86240

European-Finnish (FIN) AF: 0.371 AC: 19795 AN: 53410

Middle Eastern (MID) AF: 0.536 AC: 3092 AN: 5764

European-Non Finnish (NFE) AF: 0.433 AC: 481698 AN: 1111942

Other (OTH) AF: 0.473 AC: 28566 AN: 60390

GnomAD4 genome AF: 0.541 AC: 82269 AN: 152000 Hom.: 24604 Cov.: 32 AF XY: 0.534 AC XY: 39630 AN XY: 74276

African (AFR) AF: 0.805 AC: 33367 AN: 41470

American (AMR) AF: 0.450 AC: 6873 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 1764 AN: 3470

East Asian (EAS) AF: 0.676 AC: 3487 AN: 5162

South Asian (SAS) AF: 0.330 AC: 1592 AN: 4824

European-Finnish (FIN) AF: 0.362 AC: 3813 AN: 10546

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.437 AC: 29681 AN: 67956

Other (OTH) AF: 0.534 AC: 1125 AN: 2108

Alfa AF: 0.419 Hom.: 4004

Bravo AF: 0.562

EpiCase AF: 0.468

EpiControl AF: 0.463

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.22
DANN	Benign	0.61
PhyloP100		-4.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs509474; hg19: chr6-151336739; COSMIC: COSV66225397;