1-11790505-CA-C

Position:

• chr1-11790505-CA-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_005957.5(MTHFR):​c.*174del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,432,314 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (5 hom.)
• Consequence: MTHFR NM_005957.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.27

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00114 (174/152340) while in subpopulation NFE AF= 0.00228 (155/68026). AF 95% confidence interval is 0.00199. There are 0 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFR	NM_005957.5	c.*174del		3_prime_UTR_variant	12/12	ENST00000376590.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9	c.*174del		3_prime_UTR_variant	12/12	1	NM_005957.5	A1

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 174 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00186 AC: 2385 AN: 1279974 Hom.: 5 Cov.: 27 AF XY: 0.00181 AC XY: 1130 AN XY: 623090

Gnomad4 AFR exome AF: 0.000142

Gnomad4 AMR exome AF: 0.000423

Gnomad4 ASJ exome AF: 0.0000525

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000257

Gnomad4 NFE exome AF: 0.00224

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00114 AC: 174 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.00109 AC XY: 81 AN XY: 74494

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00228

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00140 Hom.: 0

Bravo AF: 0.00114

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neural tube defects, folate-sensitive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs776554158; hg19: chr1-11850562;