NM_005271.5:c.1403-40dupT

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_005271.5(GLUD1):​c.1403-40dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.081 (0 hom.)
• Consequence: GLUD1 NM_005271.5 intron
• Clinical Significance: Not reported in ClinVar
• 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 Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.1403-40dupT		intron	N/A	NP_005262.1	P00367-1
	GLUD1	NM_001318900.1		c.1004-40dupT		intron	N/A	NP_001305829.1	P00367-3
	GLUD1	NM_001318901.1		c.902-40dupT		intron	N/A	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.1403-40_1403-39insT		intron	N/A	ENSP00000277865.4	P00367-1
	GLUD1	ENST00000915201.1		c.1451-40_1451-39insT		intron	N/A	ENSP00000585260.1
	GLUD1	ENST00000898383.1		c.1442-40_1442-39insT		intron	N/A	ENSP00000568442.1

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 178 AN: 127562 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000359

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000847

Gnomad ASJ AF: 0.00133

Gnomad EAS AF: 0.00148

Gnomad SAS AF: 0.00129

Gnomad FIN AF: 0.00375

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00118

GnomAD4 exome AF: 0.0811 AC: 45837 AN: 565458 Hom.: 0 Cov.: 0 AF XY: 0.0817 AC XY: 24955 AN XY: 305584

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

African (AFR) AF: 0.0376 AC: 569 AN: 15120

American (AMR) AF: 0.0470 AC: 1498 AN: 31878

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 1885 AN: 17464

East Asian (EAS) AF: 0.0218 AC: 686 AN: 31438

South Asian (SAS) AF: 0.100 AC: 5602 AN: 55896

European-Finnish (FIN) AF: 0.0731 AC: 2612 AN: 35752

Middle Eastern (MID) AF: 0.0843 AC: 198 AN: 2350

European-Non Finnish (NFE) AF: 0.0881 AC: 30555 AN: 346640

Other (OTH) AF: 0.0772 AC: 2232 AN: 28920

⚠️ 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: 0.00140 AC: 179 AN: 127592 Hom.: 0 Cov.: 0 AF XY: 0.00153 AC XY: 94 AN XY: 61336

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

African (AFR) AF: 0.000358 AC: 13 AN: 36274

American (AMR) AF: 0.000846 AC: 11 AN: 13006

Ashkenazi Jewish (ASJ) AF: 0.00133 AC: 4 AN: 3004

East Asian (EAS) AF: 0.00169 AC: 8 AN: 4728

South Asian (SAS) AF: 0.00129 AC: 5 AN: 3868

European-Finnish (FIN) AF: 0.00375 AC: 26 AN: 6940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 226

European-Non Finnish (NFE) AF: 0.00193 AC: 110 AN: 57128

Other (OTH) AF: 0.00117 AC: 2 AN: 1706

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000405 Hom.: 150

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

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;