8-22404734-G-A

Position:

• chr8-22404734-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000381237.6(SLC39A14):​c.24G>A​(p.Pro8=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00947 in 1,613,480 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P8P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0076 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (89 hom.)
• Consequence: SLC39A14 ENST00000381237.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.504

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 8-22404734-G-A is Benign according to our data. Variant chr8-22404734-G-A is described in ClinVar as [Benign]. Clinvar id is 708790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.504 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0076 (1155/152000) while in subpopulation NFE AF= 0.0133 (903/68012). AF 95% confidence interval is 0.0126. There are 9 homozygotes in gnomad4. There are 519 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC39A14	NM_001128431.4	c.24G>A	p.Pro8=	synonymous_variant	2/9	ENST00000381237.6	NP_001121903.1
SLC39A14	NM_015359.6	c.24G>A	p.Pro8=	synonymous_variant	2/9	ENST00000359741.10	NP_056174.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC39A14	ENST00000359741.10	c.24G>A	p.Pro8=	synonymous_variant	2/9	2	NM_015359.6	ENSP00000352779	A2
SLC39A14	ENST00000381237.6	c.24G>A	p.Pro8=	synonymous_variant	2/9	1	NM_001128431.4	ENSP00000370635	P4

Frequencies

GnomAD3 genomes AF: 0.00760 AC: 1155 AN: 151884 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00208

Gnomad FIN AF: 0.00680

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00699 AC: 1749 AN: 250074 Hom.: 9 AF XY: 0.00731 AC XY: 989 AN XY: 135368

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.00777

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.00789

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.00852

GnomAD4 exome AF: 0.00966 AC: 14121 AN: 1461480 Hom.: 89 Cov.: 35 AF XY: 0.00964 AC XY: 7009 AN XY: 727068

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.00792

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00167

Gnomad4 FIN exome AF: 0.00878

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.00848

GnomAD4 genome AF: 0.00760 AC: 1155 AN: 152000 Hom.: 9 Cov.: 32 AF XY: 0.00698 AC XY: 519 AN XY: 74330

Gnomad4 AFR AF: 0.00198

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00208

Gnomad4 FIN AF: 0.00680

Gnomad4 NFE AF: 0.0133

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00994 Hom.: 21

Bravo AF: 0.00615

EpiCase AF: 0.0107

EpiControl AF: 0.00824

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SLC39A14: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	3.5
DANN	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs112568651; hg19: chr8-22262247;