X-71592146-C-G

Variant names:

• chrX-71592146-C-G
• rs35103538
• NM_052957.5:c.84C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_052957.5(GCNA):​c.84C>G​(p.Ser28Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. S28G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 0 hem., cov: 20)
  • Exomes 𝑓: 0.000029 (0 hom. 8 hem.)
  • Failed GnomAD Quality Control
• Consequence: GCNA NM_052957.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0640
• Publications: 0 publications found

Genes affected

GCNA (HGNC:15805): (germ cell nuclear acidic peptidase) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042909354).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052957.5. 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
	GCNA	NM_052957.5	MANE Select	c.84C>G	p.Ser28Arg	missense	Exon 3 of 13	NP_443189.1	Q96QF7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCNA	ENST00000373696.8	TSL:1 MANE Select	c.84C>G	p.Ser28Arg	missense	Exon 3 of 13	ENSP00000362800.3	Q96QF7
	GCNA	ENST00000373695.1	TSL:1	c.84C>G	p.Ser28Arg	missense	Exon 2 of 12	ENSP00000362799.1	Q96QF7
	GCNA	ENST00000917930.1		c.84C>G	p.Ser28Arg	missense	Exon 3 of 13	ENSP00000587989.1

Frequencies

GnomAD3 genomes AF: 0.0000360 AC: 4 AN: 111148 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000971

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000565

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000274 AC: 5 AN: 182453 AF XY: 0.0000448

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000725

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000490

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000293 AC: 32 AN: 1093114 Hom.: 0 Cov.: 28 AF XY: 0.0000223 AC XY: 8 AN XY: 359012

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26303

American (AMR) AF: 0.0000285 AC: 1 AN: 35122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19337

East Asian (EAS) AF: 0.000166 AC: 5 AN: 30170

South Asian (SAS) AF: 0.00 AC: 0 AN: 53880

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4125

European-Non Finnish (NFE) AF: 0.0000286 AC: 24 AN: 837737

Other (OTH) AF: 0.0000218 AC: 1 AN: 45930

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000400624), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000360 AC: 4 AN: 111148 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 33336

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30571

American (AMR) AF: 0.0000971 AC: 1 AN: 10296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3582

South Asian (SAS) AF: 0.00 AC: 0 AN: 2647

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000565 AC: 3 AN: 53124

Other (OTH) AF: 0.00 AC: 0 AN: 1504

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00585934), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000136

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.4
DANN	Benign	0.85
DEOGEN2	Benign	0.0089	T
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.064
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.013
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.57	T
Polyphen		0.0060	B
Vest4		0.16
MutPred		0.21		Loss of phosphorylation at S28 (P = 0.0283)
MVP		0.043
MPC		0.65
ClinPred		0.11	T
GERP RS		0.23
Varity_R		0.17
gMVP		0.045
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs35103538; hg19: chrX-70811996;