11-72192174-A-G

Position:

• chr11-72192174-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_016729.3(FOLR1):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FOLR1 NM_016729.3 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.60

Genes affected

FOLR1 (HGNC:3791): (folate receptor alpha) The protein encoded by this gene is a member of the folate receptor family. Members of this gene family bind folic acid and its reduced derivatives, and transport 5-methyltetrahydrofolate into cells. This gene product is a secreted protein that either anchors to membranes via a glycosyl-phosphatidylinositol linkage or exists in a soluble form. Mutations in this gene have been associated with neurodegeneration due to cerebral folate transport deficiency. Due to the presence of two promoters, multiple transcription start sites, and alternative splicing, multiple transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2009]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-72192174-A-G is Pathogenic according to our data. Variant chr11-72192174-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 393190.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOLR1	NM_016729.3	c.1A>G	p.Met1?	start_lost	1/4	ENST00000393676.5
FOLR1	NM_000802.3	c.1A>G	p.Met1?	start_lost	2/5
FOLR1	NM_016724.3	c.1A>G	p.Met1?	start_lost	3/6
FOLR1	NM_016725.3	c.1A>G	p.Met1?	start_lost	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOLR1	ENST00000393676.5	c.1A>G	p.Met1?	start_lost	1/4	1	NM_016729.3	P1
	ENST00000378140.3	n.419+6339T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 27, 2017

The c.1 A>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1 A>G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution alters the initiator Methionine codon, and the resultant protein would be described as p.Met1?" to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if a protein is produced using an alternative Methionine initiator codon. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded." -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.35	T;T;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.90	.;.;.;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Benign	-0.42	T
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.92	P;P;P;P
Vest4		0.72
MutPred		0.67		Gain of methylation at R4 (P = 0.0976);Gain of methylation at R4 (P = 0.0976);Gain of methylation at R4 (P = 0.0976);Gain of methylation at R4 (P = 0.0976);
MVP		0.85
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.88
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1057524829; hg19: chr11-71903218;