rs201141455

Variant names:

• chr10-87074533-CTA-C
• rs201141455
• NM_005271.5:c.646+16_646+17delTA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_005271.5(GLUD1):​c.646+16_646+17delTA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,451,450 control chromosomes in the GnomAD database, including 18 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (10 hom.)
• Consequence: GLUD1 NM_005271.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.370

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 10-87074533-CTA-C is Benign according to our data. Variant chr10-87074533-CTA-C is described in ClinVar as [Benign]. Clinvar id is 418235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00572 (870/152090) while in subpopulation AFR AF= 0.0186 (772/41484). AF 95% confidence interval is 0.0175. There are 8 homozygotes in gnomad4. There are 427 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 870 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLUD1	NM_005271.5	c.646+16_646+17delTA		intron_variant	Intron 4 of 12	ENST00000277865.5	NP_005262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLUD1	ENST00000277865.5	c.646+16_646+17delTA		intron_variant	Intron 4 of 12	1	NM_005271.5	ENSP00000277865.4

Frequencies

GnomAD3 genomes AF: 0.00572 AC: 870 AN: 151974 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0187

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00531

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00576

GnomAD3 exomes AF: 0.00149 AC: 375 AN: 250880 Hom.: 5 AF XY: 0.00113 AC XY: 153 AN XY: 135602

Gnomad AFR exome AF: 0.0192

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000706

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000557 AC: 724 AN: 1299360 Hom.: 10 AF XY: 0.000460 AC XY: 301 AN XY: 654814

Gnomad4 AFR exome AF: 0.0173

Gnomad4 AMR exome AF: 0.00171

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000363

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000508

Gnomad4 OTH exome AF: 0.00127

GnomAD4 genome AF: 0.00572 AC: 870 AN: 152090 Hom.: 8 Cov.: 32 AF XY: 0.00574 AC XY: 427 AN XY: 74344

Gnomad4 AFR AF: 0.0186

Gnomad4 AMR AF: 0.00531

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00571

Alfa AF: 0.00247 Hom.: 0

Bravo AF: 0.00683

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Dec 20, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GLUD1 c.646+16_646+17delTA alters non-conserved nucleotides located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0015 in 250880 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency is approximately 2391.58 fold of the estimated maximal expected allele frequency for a pathogenic variant in GLUD1 causing Congenital Hyperinsulinism phenotype (6.3e-07). To our knowledge, no occurrence of c.646+16_646+17delTA in individuals affected with Congenital Hyperinsulinism and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 418235). Based on the evidence outlined above, the variant was classified as benign. -

Dec 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hyperinsulinism-hyperammonemia syndrome Benign:2

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 29, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs201141455; hg19: chr10-88834290;