rs2230267

Positions:

• chr19-48965830-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000331825.11(FTL):​c.163T>C​(p.Leu55=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 1,613,848 control chromosomes in the GnomAD database, including 222,359 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (19872 hom., cov: 33)
  • Exomes 𝑓: 0.52 (202487 hom.)
• Consequence: FTL ENST00000331825.11 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:18
• Conservation: PhyloP100: -0.251

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 19-48965830-T-C is Benign according to our data. Variant chr19-48965830-T-C is described in ClinVar as [Benign]. Clinvar id is 156440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48965830-T-C is described in Lovd as [Benign]. Variant chr19-48965830-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.251 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FTL	NM_000146.4	c.163T>C	p.Leu55=	synonymous_variant	2/4	ENST00000331825.11	NP_000137.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FTL	ENST00000331825.11	c.163T>C	p.Leu55=	synonymous_variant	2/4	1	NM_000146.4	ENSP00000366525	P1

Frequencies

GnomAD3 genomes AF: 0.509 AC: 77408 AN: 151996 Hom.: 19855 Cov.: 33

Gnomad AFR AF: 0.482

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.522

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.540

GnomAD3 exomes AF: 0.501 AC: 125886 AN: 251284 Hom.: 32088 AF XY: 0.499 AC XY: 67846 AN XY: 135854

Gnomad AFR exome AF: 0.479

Gnomad AMR exome AF: 0.526

Gnomad ASJ exome AF: 0.570

Gnomad EAS exome AF: 0.425

Gnomad SAS exome AF: 0.396

Gnomad FIN exome AF: 0.440

Gnomad NFE exome AF: 0.541

Gnomad OTH exome AF: 0.520

GnomAD4 exome AF: 0.524 AC: 765999 AN: 1461732 Hom.: 202487 Cov.: 53 AF XY: 0.521 AC XY: 379096 AN XY: 727186

Gnomad4 AFR exome AF: 0.486

Gnomad4 AMR exome AF: 0.525

Gnomad4 ASJ exome AF: 0.574

Gnomad4 EAS exome AF: 0.423

Gnomad4 SAS exome AF: 0.397

Gnomad4 FIN exome AF: 0.443

Gnomad4 NFE exome AF: 0.541

Gnomad4 OTH exome AF: 0.519

GnomAD4 genome AF: 0.509 AC: 77466 AN: 152116 Hom.: 19872 Cov.: 33 AF XY: 0.503 AC XY: 37402 AN XY: 74348

Gnomad4 AFR AF: 0.482

Gnomad4 AMR AF: 0.521

Gnomad4 ASJ AF: 0.569

Gnomad4 EAS AF: 0.425

Gnomad4 SAS AF: 0.383

Gnomad4 FIN AF: 0.446

Gnomad4 NFE AF: 0.543

Gnomad4 OTH AF: 0.545

Alfa AF: 0.536 Hom.: 9374

Bravo AF: 0.517

Asia WGS AF: 0.390 AC: 1357 AN: 3478

EpiCase AF: 0.556

EpiControl AF: 0.562

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 74% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 69. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hereditary hyperferritinemia with congenital cataracts Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Neuroferritinopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

sporadic abdominal aortic aneurysm Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

TilsonLab, Columbia University

Sep 21, 2014

Observed frequency is 15/19 = 0.789 patients with abdominal aortic aneurysm versus heterozygosity is described in "Variation Viewer" as 0.496. -

Hereditary hyperferritinemia with congenital cataracts;C1853578:Neuroferritinopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Glycogen storage disease due to muscle and heart glycogen synthase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

L-ferritin deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	10
DANN	Benign	0.79

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: rs2230267; hg19: chr19-49469087; COSMIC: COSV53169473; COSMIC: COSV53169473;