Genetic Variant GGN:p.Arg524His (chr19-38385691-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_152657.4(GGN):c.1571G>A(p.Arg524His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. R524S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GGN
NM_152657.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.05

Variant links:

Genes affected

GGN (HGNC:18869): (gametogenetin) This gene is a germ cell-specific gene that encodes proteins that interact with POG (proliferation of germ cells). Alternatively spliced transcript variants of a similar mouse gene encode at least three different proteins, namely gametogenetin protein 1a, gametogenetin protein 2, and gametogenetin protein 3, which show a perinuclear, cytoplasmic, and nucleolar localization, respectively. These proteins regulate the localization of POG and may play a role in spermatogenesis. [provided by RefSeq, Jul 2008]

GGN links:

ENSG00000267090 (HGNC:):

ENSG00000267090 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3293891).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGN	NM_152657.4 link	c.1571G>A	p.Arg524His	missense_variant	Exon 3 of 4	ENST00000334928.11	NP_689870.3	Q86UU5-1
GGN	XM_005258619.5 link	c.1571G>A	p.Arg524His	missense_variant	Exon 3 of 4		XP_005258676.1	Q86UU5-1
GGN	XM_017026451.2 link	c.1571G>A	p.Arg524His	missense_variant	Exon 2 of 3		XP_016881940.1	Q86UU5-1
GGN	XM_011526603.3 link	c.1322G>A	p.Arg441His	missense_variant	Exon 3 of 4		XP_011524905.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GGN	ENST00000334928.11 link	c.1571G>A	p.Arg524His	missense_variant	Exon 3 of 4	1	NM_152657.4	ENSP00000334940.5	Q86UU5-1
GGN	ENST00000591809.5 link	n.113-191G>A		intron_variant	Intron 2 of 3	1
ENSG00000267090	ENST00000585411.1 link	n.170C>T		non_coding_transcript_exon_variant	Exon 1 of 2	3
GGN	ENST00000585737.1 link	n.1322G>A		non_coding_transcript_exon_variant	Exon 3 of 5	2		ENSP00000467295.1	Q86UU5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1460922

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726820

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1571G>A (p.R524H) alteration is located in exon 3 (coding exon 1) of the GGN gene. This alteration results from a G to A substitution at nucleotide position 1571, causing the arginine (R) at amino acid position 524 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.054

Eigen

Benign

0.018

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.67

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.33

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.042

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.060

Polyphen

1.0

Vest4

0.38

MutPred

0.24

Loss of methylation at R524 (P = 0.0522);

MVP

0.43

MPC

1.2

ClinPred

0.99

GERP RS

3.5

Varity_R

0.42

gMVP

0.29

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over