10-87057821-GAAAAAA-GAAAAA

Variant names:

• chr10-87057821-GA-G
• rs35186250
• NM_005271.5:c.1403-40delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_005271.5(GLUD1):​c.1403-40delT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.39 (9709 hom., cov: 0)
  • Exomes 𝑓: 0.33 (486 hom.)
  • Failed GnomAD Quality Control
• Consequence: GLUD1 NM_005271.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.237
• Publications: 1 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, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 10-87057821-GA-G is Benign according to our data. Variant chr10-87057821-GA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 435339.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.687 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLUD1	NM_005271.5	MANE Select	c.1403-40delT		intron	N/A	NP_005262.1
	GLUD1	NM_001318900.1		c.1004-40delT		intron	N/A	NP_001305829.1
	GLUD1	NM_001318901.1		c.902-40delT		intron	N/A	NP_001305830.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLUD1	ENST00000277865.5	TSL:1 MANE Select	c.1403-40delT		intron	N/A	ENSP00000277865.4
	GLUD1	ENST00000684338.1		c.1403-40delT		intron	N/A	ENSP00000507457.1
	GLUD1	ENST00000684201.1		c.1127-40delT		intron	N/A	ENSP00000507887.1

Frequencies

GnomAD3 genomes AF: 0.391 AC: 49775 AN: 127460 Hom.: 9695 Cov.: 0

Gnomad AFR AF: 0.539

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.707

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.221

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.382

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.335 AC: 186534 AN: 557504 Hom.: 486 Cov.: 0 AF XY: 0.332 AC XY: 99756 AN XY: 300520

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.407 AC: 6095 AN: 14990

American (AMR) AF: 0.392 AC: 12433 AN: 31708

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 5222 AN: 17286

East Asian (EAS) AF: 0.457 AC: 14392 AN: 31468

South Asian (SAS) AF: 0.292 AC: 16037 AN: 54906

European-Finnish (FIN) AF: 0.351 AC: 12423 AN: 35368

Middle Eastern (MID) AF: 0.303 AC: 700 AN: 2312

European-Non Finnish (NFE) AF: 0.321 AC: 109485 AN: 340906

Other (OTH) AF: 0.341 AC: 9747 AN: 28560

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.391 AC: 49820 AN: 127492 Hom.: 9709 Cov.: 0 AF XY: 0.397 AC XY: 24342 AN XY: 61298

African (AFR) AF: 0.540 AC: 19551 AN: 36232

American (AMR) AF: 0.451 AC: 5861 AN: 12986

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 754 AN: 3008

East Asian (EAS) AF: 0.707 AC: 3343 AN: 4728

South Asian (SAS) AF: 0.225 AC: 870 AN: 3864

European-Finnish (FIN) AF: 0.342 AC: 2376 AN: 6952

Middle Eastern (MID) AF: 0.223 AC: 50 AN: 224

European-Non Finnish (NFE) AF: 0.283 AC: 16166 AN: 57084

Other (OTH) AF: 0.385 AC: 655 AN: 1702

Alfa AF: 0.0933 Hom.: 150

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Apr 29, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism (auto)

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: rs35186250; hg19: chr10-88817578; COSMIC: COSV53278512; COSMIC: COSV53278512;