rs34181110

Positions:

• chr14-64425752-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005956.4(MTHFD1):​c.878G>A​(p.Arg293His) variant causes a missense change. The variant allele was found at a frequency of 0.00265 in 1,612,896 control chromosomes in the GnomAD database, including 15 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R293C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: MTHFD1 NM_005956.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3 O:1
• Conservation: PhyloP100: 3.74

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009117931).
• BP6: Variant 14-64425752-G-A is Benign according to our data. Variant chr14-64425752-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13632.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0024 (365/152242) while in subpopulation NFE AF= 0.00319 (217/68014). AF 95% confidence interval is 0.00284. There are 7 homozygotes in gnomad4. There are 181 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFD1	NM_005956.4	c.878G>A	p.Arg293His	missense_variant	10/28	ENST00000652337.1
MTHFD1	NM_001364837.1	c.878G>A	p.Arg293His	missense_variant	10/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFD1	ENST00000652337.1	c.878G>A	p.Arg293His	missense_variant	10/28		NM_005956.4	P1
	ENST00000556640.1	n.506-2773C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 365 AN: 152124 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00167 AC: 421 AN: 251428 Hom.: 1 AF XY: 0.00166 AC XY: 226 AN XY: 135900

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00273

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00268 AC: 3914 AN: 1460654 Hom.: 8 Cov.: 31 AF XY: 0.00261 AC XY: 1895 AN XY: 726644

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00237

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.000899

Gnomad4 NFE exome AF: 0.00314

Gnomad4 OTH exome AF: 0.00377

GnomAD4 genome AF: 0.00240 AC: 365 AN: 152242 Hom.: 7 Cov.: 32 AF XY: 0.00243 AC XY: 181 AN XY: 74432

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00319

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00294 Hom.: 3

Bravo AF: 0.00260

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00154 AC: 187

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	MTHFD1: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Aug 16, 2021

MTHFD1 NM_005956.3 exon 10 p.Arg293His (c.878G>A): This variant has been reported in the literature in 1 individual in association with neural tube defects, segregating with disease in 1 affected family member (Hol 1998 PMID:9611072). This variant is present in 0.3% (217/68022) of European alleles and in 7 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/14-64425752-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID: 13632). This variant amino acid (Histidine) is present in several species including multiple mammals, and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Spina bifida, folate-sensitive, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Feb 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	19
DANN	Uncertain	0.99
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.0091	T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Benign	0.24
Sift	Uncertain	0.019	D;.
Sift4G	Uncertain	0.025	D;D
Polyphen		0.040	B;.
Vest4		0.70
MVP		0.90
MPC		0.45
ClinPred		0.036	T
GERP RS		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34181110; hg19: chr14-64892470;