rs878853045

Positions:

• chr2-1912023-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP2 PP3 PP5_Very_Strong

The NM_001303052.2(MYT1L):​c.1706G>A​(p.Arg569Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYT1L NM_001303052.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.81

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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a zinc_finger_region CCHHC-type 3 (size 43) in uniprot entity MYT1L_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_001303052.2
• 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). GenCC has associacion of gene with intellectual disability, autosomal dominant 39, syndromic intellectual disability.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791
• PP5: Variant 2-1912023-C-T is Pathogenic according to our data. Variant chr2-1912023-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 235469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYT1L	NM_001303052.2	c.1706G>A	p.Arg569Gln	missense_variant	12/25	ENST00000647738.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYT1L	ENST00000647738.2	c.1706G>A	p.Arg569Gln	missense_variant	12/25		NM_001303052.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 39 Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Pediatric Genetics Clinic, Sheba Medical Center	May 13, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R567Q in MYT1L (NM_015025.4) has been previously reported as a de novo variant in an affected child (Blanchet P et al). The variant has been submitted to ClinVar as Likely Pathogenic. The p.R567Q variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R567Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 567 of MYT1L is conserved in all mammalian species. The nucleotide c.1700 in MYT1L is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 26, 2018	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as de novo in a patient with intellectual disability, plagiocephaly, 5th finger clinodactyly, an ataxic gait, hyperphagia, and cerebral atrophy [PMID 28859103, reported as p.Arg569Gln] -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 19, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28859103, 28135719, 33004838, 32579932, 34748075) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 22, 2016	- -

Intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Apr 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	.;T;.;.;.;.;.;.;.;.;.;.;.;.;T;.;T;.;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;.;D;.;D;D;D;D;D;.;.;D;.;D;D;D;D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.1	.;M;.;.;.;.;.;.;.;.;.;.;.;.;M;.;M;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
REVEL	Uncertain	0.42
Polyphen		1.0, 1.0	.;D;.;.;D;.;.;D;.;.;.;.;.;D;D;.;D;D;.;.;.
MutPred		0.67		.;Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);.;.;Loss of MoRF binding (P = 0.0174);.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);.;.;.;Loss of MoRF binding (P = 0.0174);
MVP		0.52
MPC		3.2
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.74
gMVP		0.91

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: rs878853045; hg19: chr2-1915795;