rs140574574

Variant names:

• chr11-47412022-C-T
• rs140574574
• NM_001128225.3:c.398C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-47412022-C-T
• chr11-47412022-C-A
• chr11-47412022-C-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001128225.3(SLC39A13):​c.398C>T​(p.Thr133Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,611,382 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T133T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (20 hom.)
• Consequence: SLC39A13 NM_001128225.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 2.60
• Publications: 16 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009471446).
• BP6: Variant 11-47412022-C-T is Benign according to our data. Variant chr11-47412022-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196579.
• BS2: High Homozygotes in GnomAdExome4 at 20 AR gene

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.398C>T	p.Thr133Met	missense	Exon 3 of 10	NP_001121697.2	Q96H72-1
	SLC39A13	NM_001441271.1		c.398C>T	p.Thr133Met	missense	Exon 4 of 11	NP_001428200.1
	SLC39A13	NM_152264.5		c.398C>T	p.Thr133Met	missense	Exon 3 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.398C>T	p.Thr133Met	missense	Exon 3 of 10	ENSP00000354689.4	Q96H72-1
	SLC39A13	ENST00000354884.8	TSL:1	c.398C>T	p.Thr133Met	missense	Exon 3 of 10	ENSP00000346956.4	Q96H72-2
	SLC39A13	ENST00000968896.1		c.398C>T	p.Thr133Met	missense	Exon 3 of 11	ENSP00000638955.1

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 308 AN: 152256 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00345

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00224 AC: 540 AN: 241562 AF XY: 0.00230

Gnomad AFR exome AF: 0.000458

Gnomad AMR exome AF: 0.00138

Gnomad ASJ exome AF: 0.00244

Gnomad EAS exome AF: 0.000439

Gnomad FIN exome AF: 0.000198

Gnomad NFE exome AF: 0.00359

Gnomad OTH exome AF: 0.00184

GnomAD4 exome AF: 0.00324 AC: 4726 AN: 1459008 Hom.: 20 Cov.: 32 AF XY: 0.00324 AC XY: 2348 AN XY: 725544

African (AFR) AF: 0.000718 AC: 24 AN: 33432

American (AMR) AF: 0.00135 AC: 60 AN: 44376

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 60 AN: 25986

East Asian (EAS) AF: 0.000530 AC: 21 AN: 39652

South Asian (SAS) AF: 0.00219 AC: 188 AN: 85652

European-Finnish (FIN) AF: 0.000358 AC: 19 AN: 53106

Middle Eastern (MID) AF: 0.00215 AC: 12 AN: 5578

European-Non Finnish (NFE) AF: 0.00375 AC: 4169 AN: 1110976

Other (OTH) AF: 0.00287 AC: 173 AN: 60250

GnomAD4 genome AF: 0.00202 AC: 308 AN: 152374 Hom.: 0 Cov.: 33 AF XY: 0.00177 AC XY: 132 AN XY: 74524

African (AFR) AF: 0.000625 AC: 26 AN: 41582

American (AMR) AF: 0.00144 AC: 22 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4832

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00345 AC: 235 AN: 68036

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00345 Hom.: 3

Bravo AF: 0.00212

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00361 AC: 31

ExAC AF: 0.00236 AC: 286

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	1	Connective tissue disorder (1)
-	1	-	Cutis laxa;C0011644:Scleroderma;C0026267:Mitral valve prolapse;C0027092:Myopia;C4021790:Abnormality of the skeletal system;C4025596:Abnormality of connective tissue (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome, spondylocheirodysplastic type (1)
-	-	1	not specified (1)
-	-	1	SLC39A13-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.18
Sift	Benign	0.14	T
Sift4G	Benign	0.097	T
Polyphen		0.80	P
Vest4		0.64
MVP		0.64
MPC		0.60
ClinPred		0.021	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.33
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs140574574; hg19: chr11-47433573; COSMIC: COSV61522072; COSMIC: COSV61522072;