8-22404462-GTTTTT-GTTTTTTT

Variant names:

• chr8-22404462-G-GTT
• rs61222646
• NM_001128431.4:c.-15-222_-15-221dupTT

Variant summary

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

The NM_001128431.4(SLC39A14):​c.-15-222_-15-221dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 220,984 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 0.0000076 (0 hom., cov: 20)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: SLC39A14 NM_001128431.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.139
• 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.-15-222_-15-221dupTT		intron	N/A	NP_001121903.1	Q15043-1
	SLC39A14	NM_015359.6	MANE Plus Clinical	c.-15-222_-15-221dupTT		intron	N/A	NP_056174.2	Q15043-3
	SLC39A14	NM_001351657.2		c.16-222_16-221dupTT		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.-15-234_-15-233insTT		intron	N/A	ENSP00000352779.5	Q15043-3
	SLC39A14	ENST00000381237.6	TSL:1 MANE Select	c.-15-234_-15-233insTT		intron	N/A	ENSP00000370635.1	Q15043-1
	SLC39A14	ENST00000240095.10	TSL:1	c.-15-234_-15-233insTT		intron	N/A	ENSP00000240095.6	Q15043-2

Frequencies

GnomAD3 genomes AF: 0.00000759 AC: 1 AN: 131752 Hom.: 0 Cov.: 20

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: 0.0000155

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000448 AC: 40 AN: 89232 Hom.: 0 AF XY: 0.000521 AC XY: 24 AN XY: 46108

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

African (AFR) AF: 0.00128 AC: 1 AN: 780

American (AMR) AF: 0.000659 AC: 2 AN: 3034

Ashkenazi Jewish (ASJ) AF: 0.000905 AC: 3 AN: 3316

East Asian (EAS) AF: 0.000148 AC: 1 AN: 6766

South Asian (SAS) AF: 0.000480 AC: 2 AN: 4166

European-Finnish (FIN) AF: 0.000347 AC: 2 AN: 5772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 506

European-Non Finnish (NFE) AF: 0.000455 AC: 27 AN: 59294

Other (OTH) AF: 0.000357 AC: 2 AN: 5598

⚠️ 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: 0.00000759 AC: 1 AN: 131752 Hom.: 0 Cov.: 20 AF XY: 0.0000159 AC XY: 1 AN XY: 62934

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

African (AFR) AF: 0.00 AC: 0 AN: 32842

American (AMR) AF: 0.00 AC: 0 AN: 13152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3342

East Asian (EAS) AF: 0.00 AC: 0 AN: 4676

South Asian (SAS) AF: 0.00 AC: 0 AN: 4428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000155 AC: 1 AN: 64330

Other (OTH) AF: 0.00 AC: 0 AN: 1816

⚠️ 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.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.14

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61222646; hg19: chr8-22261975;