2-1791974-C-G

Variant names:

• chr2-1791974-C-G
• rs774825001
• NM_001303052.2:c.3454G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001303052.2(MYT1L):​c.3454G>C​(p.Val1152Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,934 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MYT1L NM_001303052.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.82
• Publications: 0 publications found

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]

MYT1L Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 39

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• syndromic complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001303052.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYT1L	NM_001303052.2	MANE Select	c.3454G>C	p.Val1152Leu	missense	Exon 25 of 25	NP_001289981.1	Q9UL68-1
	MYT1L	NM_001329844.2		c.3454G>C	p.Val1152Leu	missense	Exon 26 of 26	NP_001316773.1	Q9UL68-1
	MYT1L	NM_001329845.1		c.3454G>C	p.Val1152Leu	missense	Exon 25 of 25	NP_001316774.1	Q9UL68-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYT1L	ENST00000647738.2	MANE Select	c.3454G>C	p.Val1152Leu	missense	Exon 25 of 25	ENSP00000497479.2	Q9UL68-1
	MYT1L	ENST00000428368.7	TSL:1	c.3454G>C	p.Val1152Leu	missense	Exon 26 of 26	ENSP00000396103.3	Q9UL68-1
	MYT1L	ENST00000399161.8	TSL:1	c.3448G>C	p.Val1150Leu	missense	Exon 25 of 25	ENSP00000382114.3	Q9UL68-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453934 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722792

African (AFR) AF: 0.00 AC: 0 AN: 33142

American (AMR) AF: 0.00 AC: 0 AN: 42756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25852

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 83866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109510

Other (OTH) AF: 0.00 AC: 0 AN: 60126

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.0096	T
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.31
Sift	Benign	0.25	T
Sift4G	Benign	0.29	T
Polyphen		1.0	D
Vest4		0.68
MutPred		0.30		Gain of relative solvent accessibility (P = 0.1259)
MVP		0.59
MPC		2.0
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.43
gMVP		0.97
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs774825001; hg19: chr2-1795746;