6-33201405-T-C

Position:

• chr6-33201405-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006979.3(SLC39A7):​c.160T>C​(p.Phe54Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,613,992 control chromosomes in the GnomAD database, including 149 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (6 hom., cov: 32)
  • Exomes 𝑓: 0.012 (143 hom.)
• Consequence: SLC39A7 NM_006979.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.758

Genes affected

SLC39A7 (HGNC:4927): (solute carrier family 39 member 7) The protein encoded by this gene transports zinc from the Golgi and endoplasmic reticulum to the cytoplasm. This transport may be important for activation of tyrosine kinases, some of which could be involved in cancer progression. Therefore, modulation of the encoded protein could be useful as a therapeutic agent against cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005701214).
• BP6: Variant 6-33201405-T-C is Benign according to our data. Variant chr6-33201405-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 779425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00814 (1238/152150) while in subpopulation NFE AF= 0.0132 (900/67968). AF 95% confidence interval is 0.0125. There are 6 homozygotes in gnomad4. There are 575 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC39A7	NM_006979.3	c.160T>C	p.Phe54Leu	missense_variant	1/7	ENST00000374677.8	NP_008910.2
SLC39A7	NM_001077516.2	c.160T>C	p.Phe54Leu	missense_variant	2/8		NP_001070984.1
SLC39A7	NM_001288777.2	c.52+17T>C		intron_variant			NP_001275706.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC39A7	ENST00000374677.8	c.160T>C	p.Phe54Leu	missense_variant	1/7	1	NM_006979.3	ENSP00000363809	P1

Frequencies

GnomAD3 genomes AF: 0.00815 AC: 1239 AN: 152032 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00877

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00773

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.00959

GnomAD3 exomes AF: 0.00668 AC: 1666 AN: 249574 Hom.: 8 AF XY: 0.00649 AC XY: 879 AN XY: 135404

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00623

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00733

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00775

GnomAD4 exome AF: 0.0117 AC: 17144 AN: 1461842 Hom.: 143 Cov.: 32 AF XY: 0.0112 AC XY: 8139 AN XY: 727224

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00660

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.00603

Gnomad4 NFE exome AF: 0.0142

Gnomad4 OTH exome AF: 0.0113

GnomAD4 genome AF: 0.00814 AC: 1238 AN: 152150 Hom.: 6 Cov.: 32 AF XY: 0.00773 AC XY: 575 AN XY: 74376

Gnomad4 AFR AF: 0.00234

Gnomad4 AMR AF: 0.00876

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00773

Gnomad4 NFE AF: 0.0132

Gnomad4 OTH AF: 0.00949

Alfa AF: 0.0108 Hom.: 12

Bravo AF: 0.00849

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.00398 AC: 17

ESP6500EA AF: 0.0142 AC: 121

ExAC AF: 0.00588 AC: 712

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0112

EpiControl AF: 0.00966

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SLC39A7: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0010	T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.49	N
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	0.91	N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.42	N;N
REVEL	Benign	0.15
Sift	Uncertain	0.021	D;D
Sift4G	Benign	0.64	T;T
Polyphen		0.0010	B;B
Vest4		0.19
MutPred		0.15		Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		0.47
MPC		0.52
ClinPred		0.016	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs76929655; hg19: chr6-33169182; COSMIC: COSV100807680; COSMIC: COSV100807680;