NM_001303052.2:c.1717G>A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_001303052.2(MYT1L):c.1717G>A(p.Gly573Arg) 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. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G573E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MYT1L
NM_001303052.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 7.81

Publications

5 publications found

Variant links:

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: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

MYT1L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-1910339-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 984650.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

PP5

Variant 2-1910340-C-T is Pathogenic according to our data. Variant chr2-1910340-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521634.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYT1L	NM_001303052.2 link	c.1717G>A	p.Gly573Arg	missense_variant	Exon 13 of 25	ENST00000647738.2	NP_001289981.1	Q9UL68-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYT1L	ENST00000647738.2 link	c.1717G>A	p.Gly573Arg	missense_variant	Exon 13 of 25		NM_001303052.2	ENSP00000497479.2		Q9UL68-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

246936

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1459034

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725958

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50806

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111830

Other (OTH)

AF:

0.00

AC:

AN:

60352

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 39

Pathogenic:2

Molecular Genetics Lab, CHRU Brest

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 11, 2022

MGZ Medical Genetics Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Nov 18, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 32065501, 33004838) -

Inborn genetic diseases

Uncertain:1

Mar 27, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

.;D;.;.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;.;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

D;D;D;D;.;.;D;.;D;D;D;D;D;.;.;D;.;D;D;D;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.33

MutationAssessor

Pathogenic

3.4

.;M;.;.;.;.;.;.;.;.;.;.;.;.;M;.;M;.;.;.;.

PhyloP100

7.8

PrimateAI

Pathogenic

0.84

REVEL

Pathogenic

0.83

Polyphen

1.0

.;D;.;.;D;.;.;D;.;.;.;.;.;D;D;.;D;D;.;.;.

MutPred

0.79

.;Gain of MoRF binding (P = 0.0044);Gain of MoRF binding (P = 0.0044);.;.;Gain of MoRF binding (P = 0.0044);.;.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0044);Gain of MoRF binding (P = 0.0044);Gain of MoRF binding (P = 0.0044);.;.;.;Gain of MoRF binding (P = 0.0044);

MVP

0.77

MPC

3.3

ClinPred

1.0

GERP RS

5.5

PromoterAI

-0.039

Neutral

(source)

Varity_R

0.90

gMVP

0.92

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over