2-2326035-C-G

Variant names:

• chr2-2326035-C-G
• NM_001303052.2:c.-521+4932G>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001329844.2(MYT1L):​c.-521+1G>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYT1L NM_001329844.2 splice_donor, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.74

Genes affected

MYT1L (HGNC:7623): (myelin transcription factor 1 like) This gene encodes a member of the zinc finger superfamily of transcription factors whose expression, thus far, has been found only in neuronal tissues. The encoded protein belongs to a novel class of cystein-cystein-histidine-cystein zinc finger proteins that function in the developing mammalian central nervous system. Forced expression of this gene in combination with the basic helix-loop-helix transcription factor NeuroD1 and the transcription factors POU class 3 homeobox 2 and achaete-scute family basic helix-loop-helix transcription factor 1 can convert fetal and postnatal human fibroblasts into induced neuronal cells, which are able to generate action potentials. Mutations in this gene have been associated with an autosomal dominant form of cognitive disability and with autism spectrum disorder. Alternative splicing results in multiple variants. [provided by RefSeq, Jul 2017]

MYT1L-AS1 (HGNC:49274): (MYT1L antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYT1L	NM_001303052.2	c.-521+4932G>C		intron_variant	Intron 1 of 24	ENST00000647738.2	NP_001289981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYT1L	ENST00000647738.2	c.-521+4932G>C		intron_variant	Intron 1 of 24		NM_001303052.2	ENSP00000497479.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 39 Uncertain:1

Apr 23, 2021

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The heterozygous c.-521+4932G>C variant identified in the MYT1L gene substitutes a well conserved Guanine for Cytosine within intron 1/24 of biologically relevant MYT1L transcripts (NM_015025.4 and NM_001303052.2). The MYT1L transcript has several splicing isoforms, and this nucleotide position is also a splice donor (+1) for several non-canonical transcripts with unclear biological relevance (c.-521+1G>C; transcripts NM_001329844.2, NM_001329847.2, NM_001329852.2, NM_001329846.2). This variant is absent from gnomAD(v3.1.1) suggesting it is not a common benign variant in the populations represented in that database. SpliceAI predicts this variant to lead to a loss of the donor splice site (deltascore: 0.77) and the Transcript inferred Pathogenicity Score (TraP) is 0.84, which is >99.9% score percentile for non-coding variants, strongly suggesting it is probably damaging to the transcript. This variant is absent from ClinVar and to our current knowledge has not been reported in affected individuals in the literature. Given the lack of compelling evidence for its pathogenicity, the heterozygous c.-521+4932G>C variant identified in the MYT1L gene is reported as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Uncertain	0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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: chr2-2329807;