2-1792454-A-G

Variant names:

• chr2-1792454-A-G
• NM_001303052.2:c.3287T>C

Variant summary

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

The NM_001303052.2(MYT1L):​c.3287T>C​(p.Met1096Thr) 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYT1L NM_001303052.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.22

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 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYT1L	NM_001303052.2	c.3287T>C	p.Met1096Thr	missense_variant	Exon 24 of 25	ENST00000647738.2	NP_001289981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYT1L	ENST00000647738.2	c.3287T>C	p.Met1096Thr	missense_variant	Exon 24 of 25		NM_001303052.2	ENSP00000497479.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3281T>C (p.M1094T) alteration is located in exon 24 (coding exon 19) of the MYT1L gene. This alteration results from a T to C substitution at nucleotide position 3281, causing the methionine (M) at amino acid position 1094 to be replaced by a threonine (T). 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	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;T;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.93	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	0.055	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.7	.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;M;.;M;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.2	.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T
Sift4G	Benign	0.070	.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.99, 0.99	.;D;.;.;D;D;.;.;D;.;.;.;.;.;.;D;D;.;D;D;.;.
Vest4		0.81
MutPred		0.34		.;Loss of helix (P = 0.0237);.;.;.;.;Loss of helix (P = 0.0237);.;.;Loss of helix (P = 0.0237);.;.;Loss of helix (P = 0.0237);.;.;.;Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);.;Loss of helix (P = 0.0237);.;
MVP		0.18
MPC		2.2
ClinPred		1.0	D
GERP RS		3.1
Varity_R		0.77
gMVP		1.0

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: chr2-1796226;