rs770536637

Variant names:

• chr1-11788224-C-T
• rs770536637
• NM_001010881.2:c.3924C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_001010881.2(C1orf167):​c.3924C>T​(p.His1308His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 1,303,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: C1orf167 NM_001010881.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.115
• Publications: 0 publications found

Genes affected

C1orf167 (HGNC:25262): (chromosome 1 open reading frame 167) Implicated in coronary artery disease. [provided by Alliance of Genome Resources, Apr 2022]

MTHFR (HGNC:7436): (methylenetetrahydrofolate reductase) The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]

MTHFR Gene-Disease associations (from GenCC):

• homocystinuria due to methylene tetrahydrofolate reductase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-11788224-C-T is Benign according to our data. Variant chr1-11788224-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 292197.
• BP7: Synonymous conserved (PhyloP=0.115 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010881.2. 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
	C1orf167	NM_001010881.2	MANE Select	c.3924C>T	p.His1308His	synonymous	Exon 19 of 21	NP_001010881.1	Q5SNV9-1
	MTHFR	NM_005957.5	MANE Select	c.*2456G>A		3_prime_UTR	Exon 12 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.*2456G>A		3_prime_UTR	Exon 12 of 12	NP_001317287.1	P42898-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1orf167	ENST00000688073.1	MANE Select	c.3924C>T	p.His1308His	synonymous	Exon 19 of 21	ENSP00000510540.1	Q5SNV9-1
	C1orf167	ENST00000444493.5	TSL:1	c.1422C>T	p.His474His	synonymous	Exon 8 of 10	ENSP00000398213.1	H0Y5F2
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.*2456G>A		3_prime_UTR	Exon 12 of 12	ENSP00000365775.3	P42898-1

Frequencies

GnomAD3 genomes AF: 0.000236 AC: 36 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000148 AC: 22 AN: 148972 AF XY: 0.000162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000647

Gnomad NFE exome AF: 0.000356

Gnomad OTH exome AF: 0.000233

GnomAD4 exome AF: 0.000200 AC: 230 AN: 1151450 Hom.: 0 Cov.: 32 AF XY: 0.000218 AC XY: 123 AN XY: 564492

African (AFR) AF: 0.00 AC: 0 AN: 24408

American (AMR) AF: 0.00 AC: 0 AN: 28258

Ashkenazi Jewish (ASJ) AF: 0.0000628 AC: 1 AN: 15934

East Asian (EAS) AF: 0.00 AC: 0 AN: 12832

South Asian (SAS) AF: 0.0000131 AC: 1 AN: 76194

European-Finnish (FIN) AF: 0.0000731 AC: 2 AN: 27344

Middle Eastern (MID) AF: 0.000228 AC: 1 AN: 4392

European-Non Finnish (NFE) AF: 0.000239 AC: 220 AN: 920508

Other (OTH) AF: 0.000120 AC: 5 AN: 41580

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000514 AC: 35 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000383 Hom.: 0

Bravo AF: 0.000212

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Neural tube defects, folate-sensitive (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.2
DANN	Benign	0.63
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs770536637; hg19: chr1-11848281;