2-1792348-G-T

Position:

• chr2-1792348-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001303052.2(MYT1L):​c.3393C>A​(p.Ser1131Arg) variant causes a missense 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYT1L NM_001303052.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.85

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 Uncertain_significance. Variant got 3 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). GenCC has associacion of gene with intellectual disability, autosomal dominant 39, syndromic intellectual disability.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYT1L	NM_001303052.2	c.3393C>A	p.Ser1131Arg	missense_variant	24/25	ENST00000647738.2	NP_001289981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYT1L	ENST00000647738.2	c.3393C>A	p.Ser1131Arg	missense_variant	24/25		NM_001303052.2	ENSP00000497479

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000423 AC: 1 AN: 236652 Hom.: 0 AF XY: 0.00000780 AC XY: 1 AN XY: 128254

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000934

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 14, 2021

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;T;.;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.71	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;.;.;D;.;D;D;D;D;D;D;.;.;D;.;D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.7	.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;M;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.3	.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.35
Sift	Benign	0.086	.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.47	.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0, 0.90, 1.0	.;D;.;.;P;D;.;.;D;.;.;.;.;.;.;D;D;.;D;D;.;.
Vest4		0.70
MutPred		0.36		.;Loss of disorder (P = 0.0809);.;.;.;.;Loss of disorder (P = 0.0809);.;.;Loss of disorder (P = 0.0809);.;.;Loss of disorder (P = 0.0809);.;.;.;Loss of disorder (P = 0.0809);Loss of disorder (P = 0.0809);Loss of disorder (P = 0.0809);.;Loss of disorder (P = 0.0809);.;
MVP		0.46
MPC		2.2
ClinPred		0.98	D
GERP RS		-3.6
Varity_R		0.76
gMVP		0.98

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: rs1298337593; hg19: chr2-1796120;