8-22404458-G-GT

Variant names:

• chr8-22404458-G-GT
• rs375772752
• NM_001128431.4:c.-15-235dupT

Variant summary

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

The NM_001128431.4(SLC39A14):​c.-15-235dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000463 in 280,588 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000081 (1 hom., cov: 0)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: SLC39A14 NM_001128431.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.43
• Publications: 0 publications found

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

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A14	NM_001128431.4	MANE Select	c.-15-235dupT		intron	N/A	NP_001121903.1	Q15043-1
	SLC39A14	NM_015359.6	MANE Plus Clinical	c.-15-235dupT		intron	N/A	NP_056174.2	Q15043-3
	SLC39A14	NM_001351657.2		c.16-235dupT		intron	N/A	NP_001338586.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A14	ENST00000359741.10	TSL:2 MANE Plus Clinical	c.-15-238_-15-237insT		intron	N/A	ENSP00000352779.5	Q15043-3
	SLC39A14	ENST00000381237.6	TSL:1 MANE Select	c.-15-238_-15-237insT		intron	N/A	ENSP00000370635.1	Q15043-1
	SLC39A14	ENST00000240095.10	TSL:1	c.-15-238_-15-237insT		intron	N/A	ENSP00000240095.6	Q15043-2

Frequencies

GnomAD3 genomes AF: 0.0000815 AC: 10 AN: 122760 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.0000336

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000166

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: 0.000114

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000190 AC: 3 AN: 157828 Hom.: 0 AF XY: 0.0000244 AC XY: 2 AN XY: 81828

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

African (AFR) AF: 0.000567 AC: 1 AN: 1764

American (AMR) AF: 0.00 AC: 0 AN: 5366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5696

East Asian (EAS) AF: 0.00 AC: 0 AN: 12462

South Asian (SAS) AF: 0.00 AC: 0 AN: 8966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 832

European-Non Finnish (NFE) AF: 0.0000195 AC: 2 AN: 102406

Other (OTH) AF: 0.00 AC: 0 AN: 9552

⚠️ 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.

GnomAD4 genome AF: 0.0000815 AC: 10 AN: 122760 Hom.: 1 Cov.: 0 AF XY: 0.000137 AC XY: 8 AN XY: 58580

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

African (AFR) AF: 0.0000336 AC: 1 AN: 29742

American (AMR) AF: 0.000166 AC: 2 AN: 12082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3104

East Asian (EAS) AF: 0.00 AC: 0 AN: 3652

South Asian (SAS) AF: 0.00 AC: 0 AN: 3830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.000114 AC: 7 AN: 61238

Other (OTH) AF: 0.00 AC: 0 AN: 1710

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 50

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs375772752; hg19: chr8-22261971;