Genetic Variant NM_130849.4:c.751C>T (chr8-144415027-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_130849.4(SLC39A4):c.751C>T(p.Arg251Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0436 in 1,611,662 control chromosomes in the GnomAD database, including 1,877 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R251Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.032 ( 109 hom., cov: 33)

Exomes 𝑓: 0.045 ( 1768 hom. )

Consequence

SLC39A4
NM_130849.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.318

Publications

23 publications found

Variant links:

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

SLC39A4 links:

LOC124902041 (HGNC:):

LOC124902041 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004521966).

BP6

Variant 8-144415027-G-A is Benign according to our data. Variant chr8-144415027-G-A is described in ClinVar as Benign. ClinVar VariationId is 774671.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC39A4	NM_130849.4 link	c.751C>T	p.Arg251Trp	missense_variant	Exon 4 of 12	ENST00000301305.8	NP_570901.3	Q6P5W5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC39A4	ENST00000301305.8 link	c.751C>T	p.Arg251Trp	missense_variant	Exon 4 of 12	1	NM_130849.4	ENSP00000301305.4	Q6P5W5-1
SLC39A4	ENST00000276833.9 link	c.676C>T	p.Arg226Trp	missense_variant	Exon 3 of 11	2		ENSP00000276833.5	Q6P5W5-2
SLC39A4	ENST00000526658.1 link	c.469C>T	p.Arg157Trp	missense_variant	Exon 3 of 4	3		ENSP00000434512.1	E9PQ16

Frequencies

GnomAD3 genomes

AF:

0.0319

AC:

4858

AN:

152136

Hom.:

109

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00828

Gnomad AMI

AF:

0.0702

Gnomad AMR

AF:

0.0202

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.0495

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0512

Gnomad OTH

AF:

0.0277

GnomAD4 exome

AF:

0.0448

AC:

65345

AN:

1459408

Hom.:

1768

Cov.:

AF XY:

0.0441

AC XY:

32026

AN XY:

726036

show subpopulations

African (AFR)

AF:

0.00672

AC:

225

AN:

33480

American (AMR)

AF:

0.0152

AC:

681

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00869

AC:

227

AN:

26120

East Asian (EAS)

AF:

0.000227

AC:

AN:

39696

South Asian (SAS)

AF:

0.0159

AC:

1374

AN:

86256

European-Finnish (FIN)

AF:

0.0511

AC:

2608

AN:

51068

Middle Eastern (MID)

AF:

0.00607

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0523

AC:

58128

AN:

1111944

Other (OTH)

AF:

0.0341

AC:

2058

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

4872

9744

14615

19487

24359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2102

4204

6306

8408

10510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0319

AC:

4857

AN:

152254

Hom.:

109

Cov.:

AF XY:

0.0316

AC XY:

2351

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00826

AC:

343

AN:

41546

American (AMR)

AF:

0.0201

AC:

308

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00692

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.0108

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0495

AC:

526

AN:

10622

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0512

AC:

3480

AN:

67982

Other (OTH)

AF:

0.0274

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

246

492

739

985

1231

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0440

Hom.:

123

Bravo

AF:

0.0276

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_noAF

Benign

-0.86

CADD

Benign

(source)

DEOGEN2

Benign

0.29

.;T;.

LIST_S2

Benign

0.28

T;T;T

MetaRNN

Benign

0.0045

T;T;T

PhyloP100

-0.32

Sift4G

Uncertain

0.058

T;T;.

Vest4

0.081

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.26

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over