chr2-1801755-T-G

Position:

• chr2-1801755-T-G

Variant summary

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

The NM_001303052.2(MYT1L):​c.3217A>C​(p.Lys1073Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYT1L NM_001303052.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.92

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]

(HGNC:):

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.3217A>C	p.Lys1073Gln	missense_variant	23/25	ENST00000647738.2	NP_001289981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYT1L	ENST00000647738.2	c.3217A>C	p.Lys1073Gln	missense_variant	23/25		NM_001303052.2	ENSP00000497479
	ENST00000638628.1	n.346+1453T>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

MYT1L-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 2024

The MYT1L c.3217A>C variant is predicted to result in the amino acid substitution p.Lys1073Gln. 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	Benign	0.33
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;T;.;.;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;.;.;D;.;D;D;D;D;D;D;.;.;D;.;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.2	.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;M;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.9	.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.19
Sift	Uncertain	0.027	.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.29	.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0, 0.97, 1.0	.;D;.;.;D;D;.;.;D;.;.;.;.;.;.;D;D;.;D;D;.;.
Vest4		0.33
MutPred		0.35		.;Loss of ubiquitination at K1073 (P = 0.002);.;.;.;.;Loss of ubiquitination at K1073 (P = 0.002);.;.;.;.;.;.;.;.;.;Loss of ubiquitination at K1073 (P = 0.002);Loss of ubiquitination at K1073 (P = 0.002);Loss of ubiquitination at K1073 (P = 0.002);.;.;.;
MVP		0.45
MPC		2.1
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.37
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-1805527;