19-48965508-A-T

Variant names:

• chr19-48965508-A-T
• rs139732572
• NM_000146.4:c.1A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_000146.4(FTL):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FTL NM_000146.4 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.51
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 4 pathogenic variants. Next in-frame start position is after 69 codons. Genomic position: 48965872. Lost 0.388 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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.1A>T	p.Met1?	initiator_codon	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.1A>T	p.Met1?	initiator_codon	Exon 1 of 4	ENSP00000366525.2	P02792
	FTL	ENST00000853542.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 4	ENSP00000523601.1
	FTL	ENST00000853538.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 4	ENSP00000523597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460284 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726578

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5602

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111102

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.34	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.63	T
PhyloP100		8.5
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.47
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.023	D
Polyphen		0.11	B
Vest4		0.87
MutPred		0.99		Loss of helix (P = 0.1299)
MVP		0.63
ClinPred		0.99	D
GERP RS		5.5
PromoterAI		0.015	Neutral
Varity_R		0.46
gMVP		0.20
Mutation Taster		=17/183	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139732572; hg19: chr19-49468765;