rs387906549

Variant names:

• chr11-61967589-T-A
• rs387906549
• NM_002032.3:c.-164A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_002032.3(FTH1):​c.-164A>T variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FTH1 NM_002032.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.11
• Publications: 4 publications found

Genes affected

FTH1 (HGNC:3976): (ferritin heavy chain 1) This gene encodes the heavy subunit of ferritin, 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 ferritin proteins are associated with several neurodegenerative diseases. This gene has multiple pseudogenes. Several alternatively spliced transcript variants have been observed, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

FTH1 Gene-Disease associations (from GenCC):

• neurodegeneration with brain iron accumulation 9

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen, Ambry Genetics
• hemochromatosis type 5

  Inheritance: Unknown, AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, ClinGen, Ambry Genetics

ENSG00000303745 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-61967589-T-A is Pathogenic according to our data. Variant chr11-61967589-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 16490.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002032.3. 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
	FTH1	NM_002032.3	MANE Select	c.-164A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	NP_002023.2	P02794
	FTH1	NM_002032.3	MANE Select	c.-164A>T		5_prime_UTR	Exon 1 of 4	NP_002023.2	P02794
	LOC399900	NR_187560.1		n.296T>A		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTH1	ENST00000273550.12	TSL:1 MANE Select	c.-164A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000273550.7	P02794
	FTH1	ENST00000620041.5	TSL:1	c.-75A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000484477.1	P02794
	FTH1	ENST00000273550.12	TSL:1 MANE Select	c.-164A>T		5_prime_UTR	Exon 1 of 4	ENSP00000273550.7	P02794

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 5

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hemochromatosis type 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Benign	0.96
PhyloP100		5.1
PromoterAI		-0.0084	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Mutation Taster		=4/296	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs387906549;

hg19: chr11-61735061;