3-190858939-T-C

Position:

• chr3-190858939-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001146686.3(GMNC):​c.256A>G​(p.Arg86Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000717 in 1,395,518 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: GMNC NM_001146686.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.937

Genes affected

GMNC (HGNC:40049): (geminin coiled-coil domain containing) Predicted to enable chromatin binding activity. Predicted to be involved in DNA replication; negative regulation of DNA replication; and negative regulation of cell cycle. Predicted to act upstream of or within cilium assembly. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GMNC	NM_001146686.3	c.256A>G	p.Arg86Gly	missense_variant	3/5	ENST00000442080.6	NP_001140158.1
GMNC	XR_924161.3	n.335A>G		non_coding_transcript_exon_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GMNC	ENST00000442080.6	c.256A>G	p.Arg86Gly	missense_variant	3/5	5	NM_001146686.3	ENSP00000406164	P1
GMNC	ENST00000479491.5	n.162A>G		non_coding_transcript_exon_variant	2/4	4
GMNC	ENST00000456552.1	c.*139A>G		3_prime_UTR_variant, NMD_transcript_variant	4/5	5		ENSP00000396337

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000717 AC: 10 AN: 1395518 Hom.: 0 Cov.: 28 AF XY: 0.00000726 AC XY: 5 AN XY: 688574

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: 0.00000930

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2023

The c.256A>G (p.R86G) alteration is located in exon 3 (coding exon 3) of the GMNC gene. This alteration results from a A to G substitution at nucleotide position 256, causing the arginine (R) at amino acid position 86 to be replaced by a glycine (G). 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	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.95	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.24
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.043	D
Polyphen		0.96	D
Vest4		0.65
MutPred		0.22		Gain of loop (P = 0.0013);
MVP		0.16
ClinPred		0.97	D
GERP RS		2.0
Varity_R		0.59
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1370738906; hg19: chr3-190576728;