2-1792005-A-T

Position:

• chr2-1792005-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001303052.2(MYT1L):​c.3423T>A​(p.Asp1141Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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_001303052.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYT1L. . Gene score misZ: 4.7706 (greater than the threshold 3.09). Trascript score misZ: 5.5162 (greater than threshold 3.09). The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. GenCC has associacion of the gene with intellectual disability, autosomal dominant 39, syndromic intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.04178202).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYT1L	NM_001303052.2	c.3423T>A	p.Asp1141Glu	missense_variant, splice_region_variant	25/25	ENST00000647738.2	NP_001289981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYT1L	ENST00000647738.2	c.3423T>A	p.Asp1141Glu	missense_variant, splice_region_variant	25/25		NM_001303052.2	ENSP00000497479.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2024

The c.3417T>A (p.D1139E) alteration is located in exon 25 (coding exon 20) of the MYT1L gene. This alteration results from a T to A substitution at nucleotide position 3417, causing the aspartic acid (D) at amino acid position 1139 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	17
DANN	Benign	0.82
DEOGEN2	Benign	0.015	T;.;.;.;.;.;.;.;.;.;.;T;T;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.81	T;T;T;.;T;.;T;T;T;T;.;.;.;T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.042	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.2	N;.;.;.;.;.;.;.;.;.;.;N;N;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	1.4	.;.;N;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.095
Sift	Benign	1.0	.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	1.0	.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.0	B;.;B;B;.;B;.;.;.;.;B;B;B;B;.
Vest4		0.026
MutPred		0.29		Gain of disorder (P = 0.1881);.;.;.;.;.;.;Gain of disorder (P = 0.1881);.;.;.;Gain of disorder (P = 0.1881);Gain of disorder (P = 0.1881);.;.;
MVP		0.068
MPC		0.87
ClinPred		0.20	T
GERP RS		4.7
Varity_R		0.098
gMVP		0.63

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: rs1308227334; hg19: chr2-1795777;