14-64449447-C-T

Position:

• chr14-64449447-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005956.4(MTHFD1):​c.2282C>T​(p.Thr761Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00633 in 1,613,056 control chromosomes in the GnomAD database, including 362 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. T761T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.026 (152 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (210 hom.)
• Consequence: MTHFD1 NM_005956.4 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.09

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]

ZBTB25 (HGNC:13112): (zinc finger and BTB domain containing 25) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008836538).
• BP6: Variant 14-64449447-C-T is Benign according to our data. Variant chr14-64449447-C-T is described in ClinVar as [Benign]. Clinvar id is 1166610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64449447-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFD1	NM_005956.4	c.2282C>T	p.Thr761Met	missense_variant, splice_region_variant	24/28	ENST00000652337.1
MTHFD1	NM_001364837.1	c.2282C>T	p.Thr761Met	missense_variant, splice_region_variant	24/27
ZBTB25	NM_001304508.1	c.*104G>A		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFD1	ENST00000652337.1	c.2282C>T	p.Thr761Met	missense_variant, splice_region_variant	24/28		NM_005956.4	P1

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 3973 AN: 152152 Hom.: 151 Cov.: 32

Gnomad AFR AF: 0.0868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0277

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0162

GnomAD3 exomes AF: 0.00987 AC: 2478 AN: 251140 Hom.: 83 AF XY: 0.00882 AC XY: 1198 AN XY: 135766

Gnomad AFR exome AF: 0.0911

Gnomad AMR exome AF: 0.00575

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0237

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.00427 AC: 6233 AN: 1460786 Hom.: 210 Cov.: 30 AF XY: 0.00451 AC XY: 3280 AN XY: 726696

Gnomad4 AFR exome AF: 0.0947

Gnomad4 AMR exome AF: 0.00599

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0230

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000300

Gnomad4 OTH exome AF: 0.00735

GnomAD4 genome AF: 0.0262 AC: 3984 AN: 152270 Hom.: 152 Cov.: 32 AF XY: 0.0255 AC XY: 1901 AN XY: 74464

Gnomad4 AFR AF: 0.0868

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0275

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00374 Hom.: 30

Bravo AF: 0.0296

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0892 AC: 393

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0118 AC: 1438

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	.;D
MetaRNN	Benign	0.0088	T;T
MetaSVM	Benign	-0.78	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.7	D;.
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.20
MPC		0.54
ClinPred		0.086	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs10813; hg19: chr14-64916165; COSMIC: COSV53700086; COSMIC: COSV53700086;