chr8-22404462-GT-G

Variant names:

• chr8-22404462-GT-G
• rs61222646
• NM_001128431.4:c.-15-221delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001128431.4(SLC39A14):​c.-15-221delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 219,734 control chromosomes in the GnomAD database, including 6,143 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.27 (5157 hom., cov: 20)
  • Exomes 𝑓: 0.27 (986 hom.)
• Consequence: SLC39A14 NM_001128431.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 8-22404462-GT-G is Benign according to our data. Variant chr8-22404462-GT-G is described in ClinVar as Benign. ClinVar VariationId is 1232290.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

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.-15-221delT		intron	N/A	NP_001121903.1	Q15043-1
	SLC39A14	NM_015359.6	MANE Plus Clinical	c.-15-221delT		intron	N/A	NP_056174.2	Q15043-3
	SLC39A14	NM_001351657.2		c.16-221delT		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.-15-233delT		intron	N/A	ENSP00000352779.5	Q15043-3
	SLC39A14	ENST00000381237.6	TSL:1 MANE Select	c.-15-233delT		intron	N/A	ENSP00000370635.1	Q15043-1
	SLC39A14	ENST00000240095.10	TSL:1	c.-15-233delT		intron	N/A	ENSP00000240095.6	Q15043-2

Frequencies

GnomAD3 genomes AF: 0.269 AC: 35463 AN: 131640 Hom.: 5162 Cov.: 20

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.518

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.281

GnomAD4 exome AF: 0.271 AC: 23884 AN: 88114 Hom.: 986 AF XY: 0.268 AC XY: 12197 AN XY: 45508

African (AFR) AF: 0.275 AC: 211 AN: 766

American (AMR) AF: 0.287 AC: 859 AN: 2994

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 937 AN: 3264

East Asian (EAS) AF: 0.417 AC: 2792 AN: 6698

South Asian (SAS) AF: 0.178 AC: 734 AN: 4128

European-Finnish (FIN) AF: 0.290 AC: 1660 AN: 5716

Middle Eastern (MID) AF: 0.260 AC: 130 AN: 500

European-Non Finnish (NFE) AF: 0.257 AC: 15047 AN: 58524

Other (OTH) AF: 0.274 AC: 1514 AN: 5524

GnomAD4 genome AF: 0.269 AC: 35453 AN: 131620 Hom.: 5157 Cov.: 20 AF XY: 0.274 AC XY: 17213 AN XY: 62880

African (AFR) AF: 0.145 AC: 4749 AN: 32862

American (AMR) AF: 0.329 AC: 4319 AN: 13132

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 1105 AN: 3344

East Asian (EAS) AF: 0.519 AC: 2416 AN: 4658

South Asian (SAS) AF: 0.383 AC: 1684 AN: 4398

European-Finnish (FIN) AF: 0.324 AC: 1949 AN: 6016

Middle Eastern (MID) AF: 0.345 AC: 91 AN: 264

European-Non Finnish (NFE) AF: 0.285 AC: 18290 AN: 64272

Other (OTH) AF: 0.280 AC: 511 AN: 1822

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.14
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

Other links and lift over

dbSNP: rs61222646; hg19: chr8-22261975;