rs9421572

Variant names:

• chr10-87061032-T-C
• rs9421572
• NM_005271.5:c.942A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-87061032-T-C
• chr10-87061032-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005271.5(GLUD1):​c.942A>G​(p.Leu314Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,613,134 control chromosomes in the GnomAD database, including 14,924 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (1509 hom., cov: 32)
  • Exomes 𝑓: 0.11 (13415 hom.)
• Consequence: GLUD1 NM_005271.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.168
• Publications: 19 publications found

Genes affected

GLUD1 (HGNC:4335): (glutamate dehydrogenase 1) This gene encodes glutamate dehydrogenase, which is a mitochondrial matrix enzyme that catalyzes the oxidative deamination of glutamate to alpha-ketoglutarate and ammonia. This enzyme has an important role in regulating amino acid-induced insulin secretion. It is allosterically activated by ADP and inhibited by GTP and ATP. Activating mutations in this gene are a common cause of congenital hyperinsulinism. Alternative splicing of this gene results in multiple transcript variants. The related glutamate dehydrogenase 2 gene on the human X-chromosome originated from this gene via retrotransposition and encodes a soluble form of glutamate dehydrogenase. Related pseudogenes have been identified on chromosomes 10, 18 and X. [provided by RefSeq, Jan 2016]

GLUD1 Gene-Disease associations (from GenCC):

• hyperinsulinism-hyperammonemia syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 10-87061032-T-C is Benign according to our data. Variant chr10-87061032-T-C is described in ClinVar as Benign. ClinVar VariationId is 129164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.168 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005271.5. 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
	GLUD1	NM_005271.5	MANE Select	c.942A>G	p.Leu314Leu	synonymous	Exon 7 of 13	NP_005262.1	P00367-1
	GLUD1	NM_001318900.1		c.543A>G	p.Leu181Leu	synonymous	Exon 7 of 13	NP_001305829.1	P00367-3
	GLUD1	NM_001318901.1		c.441A>G	p.Leu147Leu	synonymous	Exon 10 of 16	NP_001305830.1	P00367-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLUD1	ENST00000277865.5	TSL:1 MANE Select	c.942A>G	p.Leu314Leu	synonymous	Exon 7 of 13	ENSP00000277865.4	P00367-1
	GLUD1	ENST00000915201.1		c.990A>G	p.Leu330Leu	synonymous	Exon 7 of 13	ENSP00000585260.1
	GLUD1	ENST00000898383.1		c.981A>G	p.Leu327Leu	synonymous	Exon 7 of 13	ENSP00000568442.1

Frequencies

GnomAD3 genomes AF: 0.0938 AC: 14264 AN: 152078 Hom.: 1510 Cov.: 32

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0948

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.0807

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0928

Gnomad OTH AF: 0.110

GnomAD2 exomes AF: 0.124 AC: 31252 AN: 251474 AF XY: 0.122

Gnomad AFR exome AF: 0.0185

Gnomad AMR exome AF: 0.0712

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.589

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.0922

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.105 AC: 153756 AN: 1460938 Hom.: 13415 Cov.: 32 AF XY: 0.104 AC XY: 75703 AN XY: 726832

African (AFR) AF: 0.0164 AC: 550 AN: 33466

American (AMR) AF: 0.0761 AC: 3404 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3119 AN: 26124

East Asian (EAS) AF: 0.592 AC: 23469 AN: 39676

South Asian (SAS) AF: 0.0664 AC: 5724 AN: 86252

European-Finnish (FIN) AF: 0.146 AC: 7815 AN: 53420

Middle Eastern (MID) AF: 0.0444 AC: 256 AN: 5766

European-Non Finnish (NFE) AF: 0.0919 AC: 102124 AN: 1111160

Other (OTH) AF: 0.121 AC: 7295 AN: 60352

GnomAD4 genome AF: 0.0938 AC: 14272 AN: 152196 Hom.: 1509 Cov.: 32 AF XY: 0.0983 AC XY: 7317 AN XY: 74398

African (AFR) AF: 0.0196 AC: 814 AN: 41544

American (AMR) AF: 0.0949 AC: 1450 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 433 AN: 3472

East Asian (EAS) AF: 0.590 AC: 3056 AN: 5178

South Asian (SAS) AF: 0.0812 AC: 391 AN: 4818

European-Finnish (FIN) AF: 0.146 AC: 1545 AN: 10574

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0928 AC: 6309 AN: 68008

Other (OTH) AF: 0.114 AC: 242 AN: 2114

Alfa AF: 0.0844 Hom.: 300

Bravo AF: 0.0905

Asia WGS AF: 0.290 AC: 1005 AN: 3478

EpiCase AF: 0.0870

EpiControl AF: 0.0904

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hyperinsulinism-hyperammonemia syndrome (3)
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.5
DANN	Benign	0.76
PhyloP100		0.17
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs9421572; hg19: chr10-88820789; COSMIC: COSV53278976; COSMIC: COSV53278976;