8-22404458-G-GTTTT

Variant names:

• chr8-22404458-G-GTTTT
• rs375772752
• NM_001128431.4:c.-15-235_-15-234insTTTT

Variant summary

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

The NM_001128431.4(SLC39A14):​c.-15-235_-15-234insTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0401 in 279,522 control chromosomes in the GnomAD database, including 1,144 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.092 (1143 hom., cov: 0)
  • Exomes 𝑓: 0.00017 (1 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-GTTTT is Benign according to our data. Variant chr8-22404458-G-GTTTT is described in ClinVar as Benign. ClinVar VariationId is 1265704.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.245 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.-15-235_-15-234insTTTT		intron	N/A	NP_001121903.1	Q15043-1
	SLC39A14	NM_015359.6	MANE Plus Clinical	c.-15-235_-15-234insTTTT		intron	N/A	NP_056174.2	Q15043-3
	SLC39A14	NM_001351657.2		c.16-235_16-234insTTTT		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_-15-237insTTTT		intron	N/A	ENSP00000352779.5	Q15043-3
	SLC39A14	ENST00000381237.6	TSL:1 MANE Select	c.-15-238_-15-237insTTTT		intron	N/A	ENSP00000370635.1	Q15043-1
	SLC39A14	ENST00000240095.10	TSL:1	c.-15-238_-15-237insTTTT		intron	N/A	ENSP00000240095.6	Q15043-2

Frequencies

GnomAD3 genomes AF: 0.0918 AC: 11176 AN: 121680 Hom.: 1143 Cov.: 0

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.0180

Gnomad AMR AF: 0.0604

Gnomad ASJ AF: 0.0472

Gnomad EAS AF: 0.0999

Gnomad SAS AF: 0.0918

Gnomad FIN AF: 0.00945

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0336

Gnomad OTH AF: 0.0924

GnomAD4 exome AF: 0.000171 AC: 27 AN: 157804 Hom.: 1 AF XY: 0.000183 AC XY: 15 AN XY: 81814

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

African (AFR) AF: 0.00170 AC: 3 AN: 1764

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

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

East Asian (EAS) AF: 0.000161 AC: 2 AN: 12460

South Asian (SAS) AF: 0.000669 AC: 6 AN: 8964

European-Finnish (FIN) AF: 0.000464 AC: 5 AN: 10784

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

European-Non Finnish (NFE) AF: 0.000107 AC: 11 AN: 102390

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: 0.0918 AC: 11174 AN: 121718 Hom.: 1143 Cov.: 0 AF XY: 0.0921 AC XY: 5350 AN XY: 58118

African (AFR) AF: 0.249 AC: 7314 AN: 29322

American (AMR) AF: 0.0602 AC: 717 AN: 11908

Ashkenazi Jewish (ASJ) AF: 0.0472 AC: 146 AN: 3096

East Asian (EAS) AF: 0.0996 AC: 356 AN: 3576

South Asian (SAS) AF: 0.0909 AC: 342 AN: 3762

European-Finnish (FIN) AF: 0.00945 AC: 60 AN: 6346

Middle Eastern (MID) AF: 0.0664 AC: 15 AN: 226

European-Non Finnish (NFE) AF: 0.0337 AC: 2053 AN: 61006

Other (OTH) AF: 0.0924 AC: 157 AN: 1700

Alfa AF: 0.00527 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;