16-4812232-C-T

Variant names:

• chr16-4812232-C-T
• rs769907369
• NM_032569.4:c.1136G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_032569.4(GLYR1):​c.1136G>A​(p.Gly379Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G379V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GLYR1 NM_032569.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.29
• Publications: 3 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032569.4. 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
	GLYR1	NM_032569.4	MANE Select	c.1136G>A	p.Gly379Glu	missense	Exon 13 of 16	NP_115958.2
	GLYR1	NM_001308096.2		c.1118G>A	p.Gly373Glu	missense	Exon 13 of 16	NP_001295025.1	Q49A26-3
	GLYR1	NM_001324098.2		c.1085G>A	p.Gly362Glu	missense	Exon 12 of 15	NP_001311027.2	Q49A26-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLYR1	ENST00000321919.14	TSL:1 MANE Select	c.1136G>A	p.Gly379Glu	missense	Exon 13 of 16	ENSP00000322716.6	Q49A26-1
	GLYR1	ENST00000591451.5	TSL:1	c.1118G>A	p.Gly373Glu	missense	Exon 13 of 16	ENSP00000468328.1	Q49A26-3
	GLYR1	ENST00000589389.5	TSL:1	c.1046G>A	p.Gly349Glu	missense	Exon 11 of 14	ENSP00000466570.1	K7EMM8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249790 AF XY: 0.00000740

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460780 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726766

African (AFR) AF: 0.0000299 AC: 1 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111788

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.98	D
Vest4		0.86
MutPred		0.93		Gain of solvent accessibility (P = 0.0411)
MVP		0.76
MPC		1.6
ClinPred		0.97	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.91

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

Other links and lift over

dbSNP: rs769907369; hg19: chr16-4862233;