16-86532045-C-G

Variant names:

• chr16-86532045-C-G
• rs953140970
• NM_001159377.2:c.1118G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001159377.2(MTHFSD):​c.1118G>C​(p.Arg373Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000222 in 1,349,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: MTHFSD NM_001159377.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.166

Genes affected

MTHFSD (HGNC:25778): (methenyltetrahydrofolate synthetase domain containing) Enables RNA binding activity. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13453302).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFSD	NM_001159377.2	c.1118G>C	p.Arg373Thr	missense_variant	Exon 8 of 8	ENST00000360900.11	NP_001152849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFSD	ENST00000360900.11	c.1118G>C	p.Arg373Thr	missense_variant	Exon 8 of 8	1	NM_001159377.2	ENSP00000354152.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000222 AC: 3 AN: 1349830 Hom.: 0 Cov.: 29 AF XY: 0.00000303 AC XY: 2 AN XY: 661012

Gnomad4 AFR exome AF: 0.0000668

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000180

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1118G>C (p.R373T) alteration is located in exon 8 (coding exon 8) of the MTHFSD gene. This alteration results from a G to C substitution at nucleotide position 1118, causing the arginine (R) at amino acid position 373 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.3
DANN	Benign	0.84
DEOGEN2	Benign	0.0022	T;T;.;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.75	T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;.;.;M
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.7	N;N;.;N;N
REVEL	Benign	0.096
Sift	Benign	0.15	T;T;.;T;T
Sift4G	Benign	0.33	T;T;T;T;T
Polyphen		0.16	B;.;B;.;.
Vest4		0.14
MutPred		0.63		Loss of MoRF binding (P = 0.0064);.;.;.;Loss of MoRF binding (P = 0.0064);
MVP		0.29
MPC		0.023
ClinPred		0.055	T
GERP RS		-1.3
Varity_R		0.17
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs953140970; hg19: chr16-86565651;