X-141881570-A-G

Position:

• chrX-141881570-A-G

Variant summary

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

The NM_138702.1(MAGEC3):​c.683A>G​(p.Lys228Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,209,433 control chromosomes in the GnomAD database, including 20 homozygotes. There are 437 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (7 hom., 177 hem., cov: 23)
  • Exomes 𝑓: 0.00089 (13 hom. 260 hem.)
• Consequence: MAGEC3 NM_138702.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0290

Genes affected

MAGEC3 (HGNC:23798): (MAGE family member C3) This gene is a member of the MAGEC gene family. The members of this family are not expressed in normal tissues, except for testis, and are expressed in tumors of various histological types. The MAGEC genes are clustered on chromosome Xq26-q27. Two transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006769985).
• BP6: Variant X-141881570-A-G is Benign according to our data. Variant chrX-141881570-A-G is described in ClinVar as [Benign]. Clinvar id is 789873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-141881570-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00605 (677/111857) while in subpopulation AFR AF= 0.0196 (603/30773). AF 95% confidence interval is 0.0183. There are 7 homozygotes in gnomad4. There are 177 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGEC3	NM_138702.1	c.683A>G	p.Lys228Arg	missense_variant	4/8	ENST00000298296.1	NP_619647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGEC3	ENST00000298296.1	c.683A>G	p.Lys228Arg	missense_variant	4/8	1	NM_138702.1	ENSP00000298296.1
MAGEC3	ENST00000443323.2	c.-119+967A>G		intron_variant		1		ENSP00000438254.1

Frequencies

GnomAD3 genomes AF: 0.00604 AC: 675 AN: 111809 Hom.: 7 Cov.: 23 AF XY: 0.00515 AC XY: 175 AN XY: 33989

Gnomad AFR AF: 0.0196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.000188

Gnomad OTH AF: 0.00403

GnomAD3 exomes AF: 0.00175 AC: 319 AN: 182788 Hom.: 1 AF XY: 0.00114 AC XY: 77 AN XY: 67268

Gnomad AFR exome AF: 0.0205

Gnomad AMR exome AF: 0.000768

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000233

Gnomad OTH exome AF: 0.00222

GnomAD4 exome AF: 0.000889 AC: 976 AN: 1097576 Hom.: 13 Cov.: 31 AF XY: 0.000716 AC XY: 260 AN XY: 362942

Gnomad4 AFR exome AF: 0.0229

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000925

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000201

Gnomad4 OTH exome AF: 0.00274

GnomAD4 genome AF: 0.00605 AC: 677 AN: 111857 Hom.: 7 Cov.: 23 AF XY: 0.00520 AC XY: 177 AN XY: 34047

Gnomad4 AFR AF: 0.0196

Gnomad4 AMR AF: 0.00537

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000188

Gnomad4 OTH AF: 0.00398

Alfa AF: 0.00119 Hom.: 50

Bravo AF: 0.00797

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.0172 AC: 66

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.00199 AC: 242

EpiCase AF: 0.0000545

EpiControl AF: 0.000475

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.92	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	5.9
DANN	Benign	0.90
DEOGEN2	Benign	0.013	T
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.85	L
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.049
Sift	Benign	0.49	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.017	B
Vest4		0.11
MVP		0.10
MPC		0.076
ClinPred		0.00032	T
GERP RS		-1.8
Varity_R		0.040
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs145822629; hg19: chrX-140969356;