16-86532232-C-G

Variant names:

• chr16-86532232-C-G
• rs200853025
• NM_001159377.2:c.931G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001159377.2(MTHFSD):​c.931G>C​(p.Gly311Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTHFSD NM_001159377.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.99

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFSD	NM_001159377.2	c.931G>C	p.Gly311Arg	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.931G>C	p.Gly311Arg	missense_variant	Exon 8 of 8	1	NM_001159377.2	ENSP00000354152.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0069	T;T;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Pathogenic	3.4	M;.;.;.;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.0	D;D;.;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0040	D;D;.;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		1.0	D;.;D;.;.
Vest4		0.73
MutPred		0.75		Gain of MoRF binding (P = 0.0115);.;.;.;Gain of MoRF binding (P = 0.0115);
MVP		0.44
MPC		0.17
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.38
gMVP		0.86

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: rs200853025; hg19: chr16-86565838;