Genetic Variant FTL:c.-161C>T (chr19-48965347-C-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PP5_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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000019 ( 0 hom. )

Consequence

FTL
NM_000146.4 5_prime_UTR

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 5.78

Publications

2 publications found

Variant links:

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

FTL links:

ENSG00000305635 (HGNC:):

ENSG00000305635 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

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

Gene	Transcript	Tags	HGVSc	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.:

GnomAD4 exome

AF:

0.00000189

AC:

AN:

528044

Hom.:

Cov.:

AF XY:

0.00000350

AC XY:

AN XY:

285550

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15184

American (AMR)

AF:

0.00

AC:

AN:

33538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18886

East Asian (EAS)

AF:

0.00

AC:

AN:

31154

South Asian (SAS)

AF:

0.00

AC:

AN:

61668

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2320

European-Non Finnish (NFE)

AF:

0.00000329

AC:

AN:

303976

Other (OTH)

AF:

0.00

AC:

AN:

29138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary hyperferritinemia with congenital cataracts (2)

not provided (2)

Hereditary hyperferritinemia with congenital cataracts;C1853578:Neuroferritinopathy (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

(source)

DANN

Benign

0.97

PhyloP100

5.8

PromoterAI

-0.037

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=3/297

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over