Genetic Variant SLC39A14:c.-15-223_-15-221delTTT (chr8-22404462-GTTT-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_001128431.4(SLC39A14):c.-15-223_-15-221delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000896 in 89,310 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 20)

Exomes 𝑓: 0.000090 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SLC39A14
NM_001128431.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.00300

Publications

0 publications found

Variant links:

Genes affected

SLC39A14 (HGNC:20858): (solute carrier family 39 member 14) This gene encodes a member of the the SLC39A family of divalent metal transporters that mediates the cellular uptake of manganese, zinc, iron, and cadmium. The encoded protein contains eight transmembrane domains, a histidine-rich motif, and a metalloprotease motif, and is expressed on the plasma membrane and the endocytic vesicle membrane. It is an important transporter of nontransferrin-bound iron and a critical regulator of manganese homeostasis. Naturally occurring mutations in this gene are associated with neurodegeneration with brain iron accumulation and early-onset parkinsonism-dystonia with hypermanganesemia. [provided by RefSeq, May 2017]

SLC39A14 Gene-Disease associations (from GenCC):

hypermanganesemia with dystonia 2
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
hyperostosis cranialis interna
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

SLC39A14 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128431.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC39A14	NM_001128431.4	MANE Select	c.-15-223_-15-221delTTT	intron	N/A	NP_001121903.1	Q15043-1
SLC39A14	NM_015359.6	MANE Plus Clinical	c.-15-223_-15-221delTTT	intron	N/A	NP_056174.2	Q15043-3
SLC39A14	NM_001351657.2		c.16-223_16-221delTTT	intron	N/A	NP_001338586.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC39A14	ENST00000359741.10	TSL:2 MANE Plus Clinical	c.-15-233_-15-231delTTT	intron	N/A	ENSP00000352779.5	Q15043-3
SLC39A14	ENST00000381237.6	TSL:1 MANE Select	c.-15-233_-15-231delTTT	intron	N/A	ENSP00000370635.1	Q15043-1
SLC39A14	ENST00000240095.10	TSL:1	c.-15-233_-15-231delTTT	intron	N/A	ENSP00000240095.6	Q15043-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

131754

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000896

AC:

AN:

89310

Hom.:

AF XY:

0.0000867

AC XY:

AN XY:

46152

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

780

American (AMR)

AF:

0.00

AC:

AN:

3038

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3314

East Asian (EAS)

AF:

0.000296

AC:

AN:

6762

South Asian (SAS)

AF:

0.00

AC:

AN:

4168

European-Finnish (FIN)

AF:

0.000346

AC:

AN:

5776

Middle Eastern (MID)

AF:

0.00

AC:

AN:

502

European-Non Finnish (NFE)

AF:

0.0000505

AC:

AN:

59358

Other (OTH)

AF:

0.000178

AC:

AN:

5612

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.244

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

131754

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

62934

African (AFR)

AF:

0.00

AC:

AN:

32842

American (AMR)

AF:

0.00

AC:

AN:

13152

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3344

East Asian (EAS)

AF:

0.00

AC:

AN:

4676

South Asian (SAS)

AF:

0.00

AC:

AN:

4428

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6022

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64330

Other (OTH)

AF:

0.00

AC:

AN:

1816

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.0030

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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8-22404462-GTTTTT-GTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over