rs2236225

Variant names:

• chr14-64442127-G-A
• rs2236225
• NM_005956.4:c.1958G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-64442127-G-A
• chr14-64442127-G-C
• chr14-64442127-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001364837.1(MTHFD1):​c.1958G>A​(p.Arg653Gln) variant causes a missense change. The variant allele was found at a frequency of 0.443 in 1,613,486 control chromosomes in the GnomAD database, including 162,717 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R653W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.39 (12554 hom., cov: 32)
  • Exomes 𝑓: 0.45 (150163 hom.)
• Consequence: MTHFD1 NM_001364837.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 5.26
• Publications: 379 publications found

Genes affected

MTHFD1 (HGNC:7432): (methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1) This gene encodes a protein that possesses three distinct enzymatic activities, 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase. Each of these activities catalyzes one of three sequential reactions in the interconversion of 1-carbon derivatives of tetrahydrofolate, which are substrates for methionine, thymidylate, and de novo purine syntheses. The trifunctional enzymatic activities are conferred by two major domains, an aminoterminal portion containing the dehydrogenase and cyclohydrolase activities and a larger synthetase domain. [provided by RefSeq, Jul 2008]

MTHFD1 Gene-Disease associations (from GenCC):

• combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000272909 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6123056E-4).
• BP6: Variant 14-64442127-G-A is Benign according to our data. Variant chr14-64442127-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 13633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364837.1. 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
	MTHFD1	NM_005956.4	MANE Select	c.1958G>A	p.Arg653Gln	missense	Exon 20 of 28	NP_005947.3
	MTHFD1	NM_001364837.1		c.1958G>A	p.Arg653Gln	missense	Exon 20 of 27	NP_001351766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1	ENST00000652337.1	MANE Select	c.1958G>A	p.Arg653Gln	missense	Exon 20 of 28	ENSP00000498336.1
	MTHFD1	ENST00000545908.6	TSL:2	c.1958G>A	p.Arg653Gln	missense	Exon 20 of 27	ENSP00000438588.2
	MTHFD1	ENST00000900031.1		c.2039G>A	p.Arg680Gln	missense	Exon 21 of 29	ENSP00000570090.1

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58706 AN: 151876 Hom.: 12553 Cov.: 32

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.592

Gnomad AMR AF: 0.519

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.393

GnomAD2 exomes AF: 0.444 AC: 111611 AN: 251462 AF XY: 0.448

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.582

Gnomad ASJ exome AF: 0.437

Gnomad EAS exome AF: 0.228

Gnomad FIN exome AF: 0.451

Gnomad NFE exome AF: 0.449

Gnomad OTH exome AF: 0.442

GnomAD4 exome AF: 0.449 AC: 656233 AN: 1461492 Hom.: 150163 Cov.: 47 AF XY: 0.451 AC XY: 328125 AN XY: 727076

African (AFR) AF: 0.203 AC: 6797 AN: 33474

American (AMR) AF: 0.575 AC: 25737 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 11429 AN: 26128

East Asian (EAS) AF: 0.259 AC: 10275 AN: 39700

South Asian (SAS) AF: 0.518 AC: 44656 AN: 86244

European-Finnish (FIN) AF: 0.453 AC: 24205 AN: 53418

Middle Eastern (MID) AF: 0.421 AC: 2428 AN: 5768

European-Non Finnish (NFE) AF: 0.454 AC: 504751 AN: 1111654

Other (OTH) AF: 0.430 AC: 25955 AN: 60382

GnomAD4 genome AF: 0.386 AC: 58737 AN: 151994 Hom.: 12554 Cov.: 32 AF XY: 0.389 AC XY: 28908 AN XY: 74282

African (AFR) AF: 0.212 AC: 8776 AN: 41482

American (AMR) AF: 0.519 AC: 7935 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 1514 AN: 3470

East Asian (EAS) AF: 0.221 AC: 1142 AN: 5156

South Asian (SAS) AF: 0.505 AC: 2427 AN: 4808

European-Finnish (FIN) AF: 0.446 AC: 4698 AN: 10538

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30752 AN: 67958

Other (OTH) AF: 0.395 AC: 830 AN: 2102

Alfa AF: 0.426 Hom.: 46692

Bravo AF: 0.381

TwinsUK AF: 0.453 AC: 1678

ALSPAC AF: 0.447 AC: 1724

ESP6500AA AF: 0.214 AC: 943

ESP6500EA AF: 0.457 AC: 3934

ExAC AF: 0.435 AC: 52851

Asia WGS AF: 0.351 AC: 1223 AN: 3478

EpiCase AF: 0.448

EpiControl AF: 0.443

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia (1)
-	-	-	Neural tube defects, folate-sensitive, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	0.0034
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.00016	T
MetaSVM	Benign	-0.91	T
PhyloP100		5.3
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.12
Sift	Benign	0.17	T
Sift4G	Benign	0.15	T
Polyphen		0.33	B
Vest4		0.059
MPC		0.42
ClinPred		0.022	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=93/7	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: rs2236225; hg19: chr14-64908845; COSMIC: COSV53697812; COSMIC: COSV53697812;