11-47410315-G-T

Variant names:

• chr11-47410315-G-T
• rs121434363
• NM_001128225.3:c.221G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001128225.3(SLC39A13):​c.221G>T​(p.Gly74Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G74D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC39A13 NM_001128225.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79
• Publications: 0 publications found

Genes affected

SLC39A13 (HGNC:20859): (solute carrier family 39 member 13) This gene encodes a member of the LIV-1 subfamily of the ZIP transporter family. The encoded transmembrane protein functions as a zinc transporter. Mutations in this gene have been associated with the spondylocheiro dysplastic form of Ehlers-Danlos syndrome. Alternate transcript variants have been found for this gene. [provided by RefSeq, Jan 2016]

SLC39A13 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, spondylocheirodysplastic type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia, ClinGen
• spondyloepimetaphyseal dysplasia-abnormal dentition syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47410315-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2133.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128225.3. 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
	SLC39A13	NM_001128225.3	MANE Select	c.221G>T	p.Gly74Val	missense	Exon 2 of 10	NP_001121697.2	Q96H72-1
	SLC39A13	NM_001441271.1		c.221G>T	p.Gly74Val	missense	Exon 3 of 11	NP_001428200.1
	SLC39A13	NM_152264.5		c.221G>T	p.Gly74Val	missense	Exon 2 of 10	NP_689477.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A13	ENST00000362021.9	TSL:1 MANE Select	c.221G>T	p.Gly74Val	missense	Exon 2 of 10	ENSP00000354689.4	Q96H72-1
	SLC39A13	ENST00000354884.8	TSL:1	c.221G>T	p.Gly74Val	missense	Exon 2 of 10	ENSP00000346956.4	Q96H72-2
	SLC39A13	ENST00000968896.1		c.221G>T	p.Gly74Val	missense	Exon 2 of 11	ENSP00000638955.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 73

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.073	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.69		Gain of catalytic residue at G74 (P = 0.1654)
MVP		0.54
MPC		1.2
ClinPred		0.99	D
GERP RS		3.9
PromoterAI		-0.0048	Neutral
Varity_R		0.94
gMVP		0.92
Mutation Taster		=15/85	disease causing

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: rs121434363; hg19: chr11-47431866;