chr8-144416001-G-T

Variant names:

• chr8-144416001-G-T
• rs121434292
• NM_130849.4:c.283C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_130849.4(SLC39A4):​c.283C>A​(p.Arg95Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R95C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC39A4 NM_130849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.90
• Publications: 10 publications found

Genes affected

SLC39A4 (HGNC:17129): (solute carrier family 39 member 4) This gene encodes a member of the zinc/iron-regulated transporter-like protein (ZIP) family. The encoded protein localizes to cell membranes and is required for zinc uptake in the intestine. Mutations in this gene result in acrodermatitis enteropathica. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2013]

SLC39A4 Gene-Disease associations (from GenCC):

• acrodermatitis enteropathica

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet

LOC124902041 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-144416001-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130849.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A4	NM_130849.4	MANE Select	c.283C>A	p.Arg95Ser	missense	Exon 2 of 12	NP_570901.3
	SLC39A4	NM_017767.3		c.208C>A	p.Arg70Ser	missense	Exon 1 of 11	NP_060237.3
	SLC39A4	NM_001374839.1		c.193-582C>A		intron	N/A	NP_001361768.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A4	ENST00000301305.8	TSL:1 MANE Select	c.283C>A	p.Arg95Ser	missense	Exon 2 of 12	ENSP00000301305.4
	SLC39A4	ENST00000276833.9	TSL:2	c.208C>A	p.Arg70Ser	missense	Exon 1 of 11	ENSP00000276833.5
	SLC39A4	ENST00000526658.1	TSL:3	c.193-582C>A		intron	N/A	ENSP00000434512.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1430672 Hom.: 0 Cov.: 83 AF XY: 0.00 AC XY: 0 AN XY: 708246

African (AFR) AF: 0.00 AC: 0 AN: 33124

American (AMR) AF: 0.00 AC: 0 AN: 41034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25540

East Asian (EAS) AF: 0.00 AC: 0 AN: 38612

South Asian (SAS) AF: 0.00 AC: 0 AN: 83438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097964

Other (OTH) AF: 0.00 AC: 0 AN: 59176

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.018	D
Polyphen		0.80	P
Vest4		0.34
MutPred		0.61		Loss of methylation at R95 (P = 0.0464)
MVP		0.80
MPC		0.49
ClinPred		0.94	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.079
gMVP		0.75
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121434292; hg19: chr8-145641385;