rs2230267

Variant names:

• chr19-48965830-T-C
• rs2230267
• NM_000146.4:c.163T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000146.4(FTL):​c.163T>C​(p.Leu55Leu) 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 NM_000146.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:19
• 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
FTL	NM_000146.4	c.163T>C	p.Leu55Leu	synonymous_variant	Exon 2 of 4	ENST00000331825.11	NP_000137.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTL	ENST00000331825.11	c.163T>C	p.Leu55Leu	synonymous_variant	Exon 2 of 4	1	NM_000146.4	ENSP00000366525.2

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

GnomAD2 exomes AF: 0.501 AC: 125886 AN: 251284 AF XY: 0.499

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 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 AC: 16270 AN: 33480

Gnomad4 AMR exome AF: 0.525 AC: 23460 AN: 44718

Gnomad4 ASJ exome AF: 0.574 AC: 15012 AN: 26136

Gnomad4 EAS exome AF: 0.423 AC: 16785 AN: 39700

Gnomad4 SAS exome AF: 0.397 AC: 34258 AN: 86252

Gnomad4 FIN exome AF: 0.443 AC: 23643 AN: 53370

Gnomad4 NFE exome AF: 0.541 AC: 601971 AN: 1111918

Gnomad4 Remaining exome AF: 0.519 AC: 31354 AN: 60392

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 AC: 0.482453 AN: 0.482453

Gnomad4 AMR AF: 0.521 AC: 0.521341 AN: 0.521341

Gnomad4 ASJ AF: 0.569 AC: 0.569412 AN: 0.569412

Gnomad4 EAS AF: 0.425 AC: 0.425445 AN: 0.425445

Gnomad4 SAS AF: 0.383 AC: 0.38267 AN: 0.38267

Gnomad4 FIN AF: 0.446 AC: 0.446091 AN: 0.446091

Gnomad4 NFE AF: 0.543 AC: 0.542554 AN: 0.542554

Gnomad4 OTH AF: 0.545 AC: 0.544508 AN: 0.544508

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:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary hyperferritinemia with congenital cataracts Benign:3

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuroferritinopathy Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 21, 2014

TilsonLab, Columbia University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

L-ferritin deficiency Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary hyperferritinemia with congenital cataracts;C1853578:Neuroferritinopathy;C3810090:L-ferritin deficiency Benign:1

Apr 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	10
DANN	Benign	0.79
Mutation Taster		=100/0	polymorphism (auto)

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;