19-48965347-C-T

Variant names:

• chr19-48965347-C-T
• rs398124636
• NM_000146.4:c.-161C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 PP5_Very_Strong

The NM_000146.4(FTL):​c.-161C>T variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00000189 in 528,044 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003922342: "In vitro functional studies provide some evidence that the c.-161C>T variant may impact protein function." PMID:8233801" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: FTL NM_000146.4 5_prime_UTR
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.78
• Publications: 2 publications found

Genes affected

FTL (HGNC:3999): (ferritin light chain) This gene encodes the light subunit of the ferritin protein. Ferritin is the major intracellular iron storage protein in prokaryotes and eukaryotes. It is composed of 24 subunits of the heavy and light ferritin chains. Variation in ferritin subunit composition may affect the rates of iron uptake and release in different tissues. A major function of ferritin is the storage of iron in a soluble and nontoxic state. Defects in this light chain ferritin gene are associated with several neurodegenerative diseases and hyperferritinemia-cataract syndrome. This gene has multiple pseudogenes. [provided by RefSeq, Jul 2008]

FTL Gene-Disease associations (from GenCC):

• hereditary hyperferritinemia with congenital cataracts

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• neuroferritinopathy

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Genomics England PanelApp
• L-ferritin deficiency

  Inheritance: Unknown, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• genetic hyperferritinemia without iron overload

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000305635 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003922342: "In vitro functional studies provide some evidence that the c.-161C>T variant may impact protein function." PMID:8233801; SCV001199418: Experimental studies have shown that this variant affects FTL function (PMID: 8233801).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-48965347-C-T is Pathogenic according to our data. Variant chr19-48965347-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000146.4. 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
	FTL	NM_000146.4	MANE Select	c.-161C>T		5_prime_UTR	Exon 1 of 4	NP_000137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTL	ENST00000331825.11	TSL:1 MANE Select	c.-161C>T		5_prime_UTR	Exon 1 of 4	ENSP00000366525.2	P02792
	FTL	ENST00000853542.1		c.-161C>T		5_prime_UTR	Exon 1 of 4	ENSP00000523601.1
	FTL	ENST00000853538.1		c.-161C>T		5_prime_UTR	Exon 1 of 4	ENSP00000523597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000189 AC: 1 AN: 528044 Hom.: 0 Cov.: 4 AF XY: 0.00000350 AC XY: 1 AN XY: 285550

African (AFR) AF: 0.00 AC: 0 AN: 15184

American (AMR) AF: 0.00 AC: 0 AN: 33538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18886

East Asian (EAS) AF: 0.00 AC: 0 AN: 31154

South Asian (SAS) AF: 0.00 AC: 0 AN: 61668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2320

European-Non Finnish (NFE) AF: 0.00000329 AC: 1 AN: 303976

Other (OTH) AF: 0.00 AC: 0 AN: 29138

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary hyperferritinemia with congenital cataracts (2)
2	-	-	not provided (2)
1	-	-	Hereditary hyperferritinemia with congenital cataracts;C1853578:Neuroferritinopathy (1)
1	-	-	Hereditary hyperferritinemia with congenital cataracts;C1853578:Neuroferritinopathy;C3810090:L-ferritin deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Benign	0.97
PhyloP100		5.8
PromoterAI		-0.037	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=3/297	disease causing (ClinVar)

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: rs398124636; hg19: chr19-49468604;