2-1801726-C-T

Variant names:

• chr2-1801726-C-T
• rs2034892543
• NM_001303052.2:c.3246G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001303052.2(MYT1L):​c.3246G>A​(p.Met1082Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYT1L NM_001303052.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82

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]

ENSG00000284600 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MYT1L gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. Gene score misZ: 4.7706 (above the threshold of 3.09). Trascript score misZ: 5.5162 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 39, syndromic intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21120885).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYT1L	NM_001303052.2	c.3246G>A	p.Met1082Ile	missense_variant	Exon 23 of 25	ENST00000647738.2	NP_001289981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYT1L	ENST00000647738.2	c.3246G>A	p.Met1082Ile	missense_variant	Exon 23 of 25		NM_001303052.2	ENSP00000497479.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MYT1L-related disorder Uncertain:1

Sep 29, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYT1L c.3246G>A variant is predicted to result in the amino acid substitution p.Met1082Ile. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Benign	0.042	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;T;.;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;.;.;D;.;D;D;D;D;D;D;.;.;D;.;D;D;D
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.86	.;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;L;.;L;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.5	.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.10
Sift	Benign	0.37	.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.48	.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.085, 0.0010, 0.14	.;B;.;.;B;B;.;.;B;.;.;.;.;.;.;B;B;.;B;B;.;.
Vest4		0.36
MutPred		0.32		.;Loss of MoRF binding (P = 0.1555);.;.;.;.;Loss of MoRF binding (P = 0.1555);.;.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.1555);Loss of MoRF binding (P = 0.1555);Loss of MoRF binding (P = 0.1555);.;.;.;
MVP		0.12
MPC		1.1
ClinPred		0.80	D
GERP RS		5.0
Varity_R		0.34
gMVP		0.94

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

LitVar

Other links and lift over

dbSNP: rs2034892543; hg19: chr2-1805498; COSMIC: COSV105333730;