chr8-144415966-G-T

Variant names:

• chr8-144415966-G-T
• rs121434290
• NM_130849.4:c.318C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_130849.4(SLC39A4):​c.318C>A​(p.Asn106Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. N106N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC39A4 NM_130849.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.220
• Publications: 6 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: Genomics England PanelApp, Ambry Genetics, Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen

LOC124902041 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-144415966-G-T is Pathogenic according to our data. Variant chr8-144415966-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3540.Status of the report is no_assertion_criteria_provided, 0 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A4	NM_130849.4	MANE Select	c.318C>A	p.Asn106Lys	missense	Exon 2 of 12	NP_570901.3	Q6P5W5-1
	SLC39A4	NM_017767.3		c.243C>A	p.Asn81Lys	missense	Exon 1 of 11	NP_060237.3	Q6P5W5-2
	SLC39A4	NM_001374839.1		c.193-547C>A		intron	N/A	NP_001361768.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A4	ENST00000301305.8	TSL:1 MANE Select	c.318C>A	p.Asn106Lys	missense	Exon 2 of 12	ENSP00000301305.4	Q6P5W5-1
	SLC39A4	ENST00000276833.9	TSL:2	c.243C>A	p.Asn81Lys	missense	Exon 1 of 11	ENSP00000276833.5	Q6P5W5-2
	SLC39A4	ENST00000526658.1	TSL:3	c.193-547C>A		intron	N/A	ENSP00000434512.1	E9PQ16

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1443116 Hom.: 0 Cov.: 83 AF XY: 0.00 AC XY: 0 AN XY: 716466

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.00 AC: 0 AN: 42184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25688

East Asian (EAS) AF: 0.00 AC: 0 AN: 39106

South Asian (SAS) AF: 0.00 AC: 0 AN: 84052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105326

Other (OTH) AF: 0.00 AC: 0 AN: 59700

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary acrodermatitis enteropathica (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.22
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.083
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.015	D
Polyphen		0.42	B
Vest4		0.084
MutPred		0.41		Gain of ubiquitination at N106 (P = 0.0192)
MVP		0.53
MPC		0.25
ClinPred		0.28	T
GERP RS		2.6
Varity_R		0.062
gMVP		0.61
Mutation Taster		=39/61	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121434290; hg19: chr8-145641350;