rs375772752

Variant names:

• chr8-22404458-G-GTTT
• rs375772752
• NM_001128431.4:c.-15-237_-15-235dupTTT

Your query was ambiguous. Multiple possible variants found:

• chr8-22404458-G-GTTT
• chr8-22404458-G-GTTTT
• chr8-22404458-G-GT
• chr8-22404458-G-GTT
• chr8-22404458-G-GTTTTT
• chr8-22404458-G-GTTTTTT
• chr8-22404458-G-GTTTTTTT
• chr8-22404458-G-GTTTTTTTTTT
• chr8-22404458-G-GTTTTTTTTTTT
• chr8-22404458-G-GTTTTTTTTTTTT
• chr8-22404458-G-GTTTTTTTTTTTTTT

Variant summary

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

The NM_001128431.4(SLC39A14):​c.-15-237_-15-235dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0697 in 278,884 control chromosomes in the GnomAD database, including 1,806 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (1806 hom., cov: 0)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: SLC39A14 NM_001128431.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 8-22404458-G-GTTT is Benign according to our data. Variant chr8-22404458-G-GTTT is described in ClinVar as Benign. ClinVar VariationId is 1235882.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.248 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.-15-237_-15-235dupTTT		intron	N/A	NP_001121903.1	Q15043-1
	SLC39A14	NM_015359.6	MANE Plus Clinical	c.-15-237_-15-235dupTTT		intron	N/A	NP_056174.2	Q15043-3
	SLC39A14	NM_001351657.2		c.16-237_16-235dupTTT		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_-15-237insTTT		intron	N/A	ENSP00000352779.5	Q15043-3
	SLC39A14	ENST00000381237.6	TSL:1 MANE Select	c.-15-238_-15-237insTTT		intron	N/A	ENSP00000370635.1	Q15043-1
	SLC39A14	ENST00000240095.10	TSL:1	c.-15-238_-15-237insTTT		intron	N/A	ENSP00000240095.6	Q15043-2

Frequencies

GnomAD3 genomes AF: 0.160 AC: 19353 AN: 121076 Hom.: 1804 Cov.: 0

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.0883

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.0864

Gnomad SAS AF: 0.0730

Gnomad FIN AF: 0.0922

Gnomad MID AF: 0.0772

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.133

GnomAD4 exome AF: 0.000412 AC: 65 AN: 157766 Hom.: 0 AF XY: 0.000379 AC XY: 31 AN XY: 81804

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

African (AFR) AF: 0.00 AC: 0 AN: 1764

American (AMR) AF: 0.000186 AC: 1 AN: 5364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5692

East Asian (EAS) AF: 0.000401 AC: 5 AN: 12458

South Asian (SAS) AF: 0.000112 AC: 1 AN: 8964

European-Finnish (FIN) AF: 0.00102 AC: 11 AN: 10780

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

European-Non Finnish (NFE) AF: 0.000430 AC: 44 AN: 102376

Other (OTH) AF: 0.000315 AC: 3 AN: 9536

⚠️ 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: 0.160 AC: 19364 AN: 121118 Hom.: 1806 Cov.: 0 AF XY: 0.152 AC XY: 8804 AN XY: 57766

African (AFR) AF: 0.252 AC: 7420 AN: 29406

American (AMR) AF: 0.0881 AC: 1051 AN: 11926

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 353 AN: 3082

East Asian (EAS) AF: 0.0862 AC: 309 AN: 3584

South Asian (SAS) AF: 0.0726 AC: 275 AN: 3786

European-Finnish (FIN) AF: 0.0922 AC: 569 AN: 6172

Middle Eastern (MID) AF: 0.0759 AC: 17 AN: 224

European-Non Finnish (NFE) AF: 0.150 AC: 9044 AN: 60464

Other (OTH) AF: 0.133 AC: 226 AN: 1698

Alfa AF: 0.0468 Hom.: 50

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		1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs375772752; hg19: chr8-22261971;