chr1-11801333-A-AGGGTCACCTGCTGGGTGCCAGGTCACGTCTATGTAGAGG

Variant names:

• chr1-11801333-A-AGGGTCACCTGCTGGGTGCCAGGTCACGTCTATGTAGAGG
• rs786204010
• NM_005957.5:c.264_302dupCCTCTACATAGACGTGACCTGGCACCCAGCAGGTGACCC

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM4 PP3 PP5_Moderate

The NM_005957.5(MTHFR):​c.264_302dupCCTCTACATAGACGTGACCTGGCACCCAGCAGGTGACCC​(p.Pro101_Gly102insLeuTyrIleAspValThrTrpHisProAlaGlyAspPro) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MTHFR NM_005957.5 disruptive_inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.20
• Publications: 0 publications found

Genes affected

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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_005957.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 1-11801333-A-AGGGTCACCTGCTGGGTGCCAGGTCACGTCTATGTAGAGG is Pathogenic according to our data. Variant chr1-11801333-A-AGGGTCACCTGCTGGGTGCCAGGTCACGTCTATGTAGAGG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 187871.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005957.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	NM_005957.5	MANE Select	c.264_302dupCCTCTACATAGACGTGACCTGGCACCCAGCAGGTGACCC	p.Pro101_Gly102insLeuTyrIleAspValThrTrpHisProAlaGlyAspPro	disruptive_inframe_insertion	Exon 3 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.387_425dupCCTCTACATAGACGTGACCTGGCACCCAGCAGGTGACCC	p.Pro142_Gly143insLeuTyrIleAspValThrTrpHisProAlaGlyAspPro	disruptive_inframe_insertion	Exon 3 of 12	NP_001317287.1
	MTHFR	NM_001410750.1		c.384_422dupCCTCTACATAGACGTGACCTGGCACCCAGCAGGTGACCC	p.Pro141_Gly142insLeuTyrIleAspValThrTrpHisProAlaGlyAspPro	disruptive_inframe_insertion	Exon 3 of 12	NP_001397679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.264_302dupCCTCTACATAGACGTGACCTGGCACCCAGCAGGTGACCC	p.Pro101_Gly102insLeuTyrIleAspValThrTrpHisProAlaGlyAspPro	disruptive_inframe_insertion	Exon 3 of 12	ENSP00000365775.3
	MTHFR	ENST00000423400.7	TSL:1	c.384_422dupCCTCTACATAGACGTGACCTGGCACCCAGCAGGTGACCC	p.Pro141_Gly142insLeuTyrIleAspValThrTrpHisProAlaGlyAspPro	disruptive_inframe_insertion	Exon 3 of 12	ENSP00000398908.3
	MTHFR	ENST00000376592.6	TSL:1	c.264_302dupCCTCTACATAGACGTGACCTGGCACCCAGCAGGTGACCC	p.Pro101_Gly102insLeuTyrIleAspValThrTrpHisProAlaGlyAspPro	disruptive_inframe_insertion	Exon 3 of 12	ENSP00000365777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:2

Nov 12, 2021

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

University Children's Hospital, University of Zurich

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2
Mutation Taster		=51/49	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786204010; hg19: chr1-11861390;