14-64400804-C-T

Variant names:

• chr14-64400804-C-T
• rs151019303
• NM_005956.4:c.53C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005956.4(MTHFD1):​c.53C>T​(p.Ala18Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00385 in 1,612,920 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A18A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (16 hom.)
• Consequence: MTHFD1 NM_005956.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.40
• Publications: 12 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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008382082).
• BP6: Variant 14-64400804-C-T is Benign according to our data. Variant chr14-64400804-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 791428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00324 (493/152266) while in subpopulation NFE AF = 0.00479 (326/68010). AF 95% confidence interval is 0.00437. There are 3 homozygotes in GnomAd4. There are 223 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005956.4. 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
	MTHFD1	NM_005956.4	MANE Select	c.53C>T	p.Ala18Val	missense	Exon 2 of 28	NP_005947.3
	MTHFD1	NM_001364837.1		c.53C>T	p.Ala18Val	missense	Exon 2 of 27	NP_001351766.1	F5H2F4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1	ENST00000652337.1	MANE Select	c.53C>T	p.Ala18Val	missense	Exon 2 of 28	ENSP00000498336.1	P11586
	MTHFD1	ENST00000555252.5	TSL:1	n.170C>T		non_coding_transcript_exon	Exon 2 of 17
	MTHFD1	ENST00000545908.6	TSL:2	c.53C>T	p.Ala18Val	missense	Exon 2 of 27	ENSP00000438588.2	F5H2F4

Frequencies

GnomAD3 genomes AF: 0.00323 AC: 492 AN: 152148 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00478

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00346 AC: 868 AN: 250952 AF XY: 0.00351

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00411

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00391 AC: 5718 AN: 1460654 Hom.: 16 Cov.: 30 AF XY: 0.00404 AC XY: 2935 AN XY: 726678

African (AFR) AF: 0.000657 AC: 22 AN: 33466

American (AMR) AF: 0.00275 AC: 123 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 421 AN: 26106

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39690

South Asian (SAS) AF: 0.00246 AC: 212 AN: 86098

European-Finnish (FIN) AF: 0.000581 AC: 31 AN: 53402

Middle Eastern (MID) AF: 0.0108 AC: 62 AN: 5766

European-Non Finnish (NFE) AF: 0.00411 AC: 4563 AN: 1111076

Other (OTH) AF: 0.00466 AC: 281 AN: 60346

GnomAD4 genome AF: 0.00324 AC: 493 AN: 152266 Hom.: 3 Cov.: 32 AF XY: 0.00300 AC XY: 223 AN XY: 74454

African (AFR) AF: 0.000914 AC: 38 AN: 41554

American (AMR) AF: 0.00288 AC: 44 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00479 AC: 326 AN: 68010

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00355 Hom.: 3

Bravo AF: 0.00330

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00337 AC: 409

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00692

EpiControl AF: 0.00641

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	MTHFD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Benign	0.93
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.4
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.038
Sift	Benign	0.047	D
Sift4G	Benign	0.079	T
Polyphen		0.034	B
Vest4		0.23
MVP		0.32
MPC		0.36
ClinPred		0.0040	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=93/7	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: rs151019303; hg19: chr14-64867522; COSMIC: COSV53699028;