5-135535459-T-TCCGG

Variant names:

• chr5-135535459-T-TCCGG
• NM_006161.3:c.228_231dupCCGG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_006161.3(NEUROG1):​c.228_231dupCCGG​(p.Thr78ProfsTer122) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NEUROG1 NM_006161.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -10.3

Genes affected

NEUROG1 (HGNC:7764): (neurogenin 1) Enables E-box binding activity and protein homodimerization activity. Involved in several processes, including animal organ morphogenesis; cranial nerve development; and hard palate morphogenesis. Predicted to be located in neuronal cell body. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000250167 (HGNC:):

SLC25A48 (HGNC:30451): (solute carrier family 25 member 48) Predicted to enable acyl carnitine transmembrane transporter activity. Predicted to be involved in acyl carnitine transport and amino acid transport. Predicted to be located in mitochondrial inner membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.676 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-135535459-T-TCCGG is Pathogenic according to our data. Variant chr5-135535459-T-TCCGG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1300181.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEUROG1	NM_006161.3	c.228_231dupCCGG	p.Thr78ProfsTer122	frameshift_variant	Exon 1 of 1	ENST00000314744.6	NP_006152.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEUROG1	ENST00000314744.6	c.228_231dupCCGG	p.Thr78ProfsTer122	frameshift_variant	Exon 1 of 1	6	NM_006161.3	ENSP00000317580.4
ENSG00000250167	ENST00000698884.1	n.496+48694_496+48697dupGCCG		intron_variant	Intron 3 of 5
SLC25A48	ENST00000698885.1	n.364+25707_364+25710dupGCCG		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

See cases Pathogenic:1

Feb 17, 2021

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

A homozygous frameshift variation in exon 1 of the NEUROG1 gene that results in a frameshift and premature truncation of the protein 122 amino acids downstream of Threonine to codon 78 was detected. The observed variant c.228_231dup(p.Thr78ProfsTer122) has not been reported in the 1000 genomes and gnomAD databases. The reference codon is conserved across species. Segregation analysis showed parents to be heterozygote carriers and affected sibling to be homozygous mutant for the variant. In summary, the variant meets our criteria to be classified as likely pathogenic variant. -

Cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay Pathogenic:1

Aug 16, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-134871149;