2-1943142-A-G

Variant names:

• chr2-1943142-A-G
• rs3748988
• NM_001303052.2:c.345T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001303052.2(MYT1L):​c.345T>C​(p.Asp115Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,531,704 control chromosomes in the GnomAD database, including 112,928 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.45 (16289 hom., cov: 27)
  • Exomes 𝑓: 0.37 (96639 hom.)
• Consequence: MYT1L NM_001303052.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -1.59
• Publications: 16 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: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-1943142-A-G is Benign according to our data. Variant chr2-1943142-A-G is described in ClinVar as Benign. ClinVar VariationId is 1174838.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYT1L	NM_001303052.2	c.345T>C	p.Asp115Asp	synonymous_variant	Exon 9 of 25	ENST00000647738.2	NP_001289981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYT1L	ENST00000647738.2	c.345T>C	p.Asp115Asp	synonymous_variant	Exon 9 of 25		NM_001303052.2	ENSP00000497479.2

Frequencies

GnomAD3 genomes AF: 0.447 AC: 66766 AN: 149422 Hom.: 16250 Cov.: 27

Gnomad AFR AF: 0.650

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.632

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.417

GnomAD2 exomes AF: 0.390 AC: 60127 AN: 154224 AF XY: 0.385

Gnomad AFR exome AF: 0.652

Gnomad AMR exome AF: 0.335

Gnomad ASJ exome AF: 0.368

Gnomad EAS exome AF: 0.637

Gnomad FIN exome AF: 0.379

Gnomad NFE exome AF: 0.352

Gnomad OTH exome AF: 0.369

GnomAD4 exome AF: 0.367 AC: 507688 AN: 1382168 Hom.: 96639 Cov.: 28 AF XY: 0.366 AC XY: 249711 AN XY: 682880

African (AFR) AF: 0.657 AC: 20491 AN: 31192

American (AMR) AF: 0.336 AC: 11979 AN: 35688

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 9164 AN: 25060

East Asian (EAS) AF: 0.622 AC: 22188 AN: 35664

South Asian (SAS) AF: 0.358 AC: 28246 AN: 78858

European-Finnish (FIN) AF: 0.383 AC: 18960 AN: 49454

Middle Eastern (MID) AF: 0.354 AC: 2005 AN: 5664

European-Non Finnish (NFE) AF: 0.350 AC: 372233 AN: 1063026

Other (OTH) AF: 0.390 AC: 22422 AN: 57562

GnomAD4 genome AF: 0.447 AC: 66845 AN: 149536 Hom.: 16289 Cov.: 27 AF XY: 0.447 AC XY: 32505 AN XY: 72790

African (AFR) AF: 0.650 AC: 26452 AN: 40672

American (AMR) AF: 0.337 AC: 5038 AN: 14948

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 1278 AN: 3452

East Asian (EAS) AF: 0.631 AC: 3173 AN: 5028

South Asian (SAS) AF: 0.369 AC: 1715 AN: 4648

European-Finnish (FIN) AF: 0.392 AC: 3932 AN: 10040

Middle Eastern (MID) AF: 0.356 AC: 104 AN: 292

European-Non Finnish (NFE) AF: 0.356 AC: 24034 AN: 67484

Other (OTH) AF: 0.413 AC: 854 AN: 2066

Alfa AF: 0.374 Hom.: 17313

Bravo AF: 0.453

Asia WGS AF: 0.494 AC: 1714 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.066
DANN	Benign	0.21
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs3748988; hg19: chr2-1946914; COSMIC: COSV67734138;