16-4814563-C-T

Variant names:

• chr16-4814563-C-T
• rs200221747
• NM_032569.4:c.991G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032569.4(GLYR1):​c.991G>A​(p.Val331Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. V331L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: GLYR1 NM_032569.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.43

Genes affected

GLYR1 (HGNC:24434): (glyoxylate reductase 1 homolog) Enables DNA binding activity; methylated histone binding activity; and nucleosome binding activity. Involved in positive regulation of histone acetylation and positive regulation of transcription by RNA polymerase II. Located in cytosol and nucleoplasm. Part of nucleosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLYR1	NM_032569.4	c.991G>A	p.Val331Met	missense_variant	Exon 11 of 16	ENST00000321919.14	NP_115958.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLYR1	ENST00000321919.14	c.991G>A	p.Val331Met	missense_variant	Exon 11 of 16	1	NM_032569.4	ENSP00000322716.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251394 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461564 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727052

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.991G>A (p.V331M) alteration is located in exon 11 (coding exon 11) of the GLYR1 gene. This alteration results from a G to A substitution at nucleotide position 991, causing the valine (V) at amino acid position 331 to be replaced by a methionine (M). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	.;T;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	3.2	.;M;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.94	N;N;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.90
MutPred		0.84		.;Gain of ubiquitination at K335 (P = 0.068);.;
MVP		0.67
MPC		1.7
ClinPred		0.78	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.63
gMVP		0.77

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: rs200221747; hg19: chr16-4864564; COSMIC: COSV58926549; COSMIC: COSV58926549;