NM_001159377.2:c.1097G>C

Variant names:

• chr16-86532066-C-G
• rs372334535
• NM_001159377.2:c.1097G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001159377.2(MTHFSD):​c.1097G>C​(p.Arg366Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R366C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MTHFSD NM_001159377.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.670
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34217677).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFSD	NM_001159377.2	c.1097G>C	p.Arg366Pro	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.1097G>C	p.Arg366Pro	missense_variant	Exon 8 of 8	1	NM_001159377.2	ENSP00000354152.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0016	T;T;.;.;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.86	D;D;D;D;D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.34	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.;.;.;L
PhyloP100		-0.67
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.93	N;N;.;N;N
REVEL	Benign	0.082
Sift	Benign	0.071	T;T;.;T;T
Sift4G	Benign	0.26	T;T;T;T;T
Polyphen		0.94	P;.;P;.;.
Vest4		0.27
MutPred		0.53		Loss of MoRF binding (P = 6e-04);.;.;.;Loss of MoRF binding (P = 6e-04);
MVP		0.32
MPC		0.060
ClinPred		0.79	D
GERP RS		-3.9
Varity_R		0.84
gMVP		0.66

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: rs372334535; hg19: chr16-86565672;