rs3748989

Variant names:

• chr2-1943196-C-T
• rs3748989
• NM_001303052.2:c.291G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001303052.2(MYT1L):​c.291G>A​(p.Glu97Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,551,574 control chromosomes in the GnomAD database, including 9,420 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1122 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8298 hom.)
• Consequence: MYT1L NM_001303052.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.592
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 2-1943196-C-T is Benign according to our data. Variant chr2-1943196-C-T is described in ClinVar as Benign. ClinVar VariationId is 1266661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.592 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYT1L	NM_001303052.2	c.291G>A	p.Glu97Glu	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.291G>A	p.Glu97Glu	synonymous_variant	Exon 9 of 25		NM_001303052.2	ENSP00000497479.2

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17208 AN: 151834 Hom.: 1122 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.0701

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.0900

Gnomad OTH AF: 0.100

GnomAD2 exomes AF: 0.119 AC: 18339 AN: 154706 AF XY: 0.116

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.0678

Gnomad EAS exome AF: 0.331

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.0907

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.101 AC: 141877 AN: 1399620 Hom.: 8298 Cov.: 33 AF XY: 0.100 AC XY: 69378 AN XY: 690346

African (AFR) AF: 0.137 AC: 4325 AN: 31614

American (AMR) AF: 0.113 AC: 4035 AN: 35712

Ashkenazi Jewish (ASJ) AF: 0.0659 AC: 1660 AN: 25180

East Asian (EAS) AF: 0.313 AC: 11178 AN: 35762

South Asian (SAS) AF: 0.109 AC: 8623 AN: 79234

European-Finnish (FIN) AF: 0.114 AC: 5615 AN: 49418

Middle Eastern (MID) AF: 0.0863 AC: 492 AN: 5700

European-Non Finnish (NFE) AF: 0.0922 AC: 99474 AN: 1078912

Other (OTH) AF: 0.111 AC: 6475 AN: 58088

GnomAD4 genome AF: 0.113 AC: 17219 AN: 151954 Hom.: 1122 Cov.: 32 AF XY: 0.115 AC XY: 8514 AN XY: 74248

African (AFR) AF: 0.134 AC: 5564 AN: 41418

American (AMR) AF: 0.105 AC: 1603 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0701 AC: 243 AN: 3468

East Asian (EAS) AF: 0.320 AC: 1642 AN: 5132

South Asian (SAS) AF: 0.116 AC: 556 AN: 4800

European-Finnish (FIN) AF: 0.111 AC: 1176 AN: 10568

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0900 AC: 6116 AN: 67992

Other (OTH) AF: 0.0990 AC: 209 AN: 2112

Alfa AF: 0.0980 Hom.: 2251

Bravo AF: 0.116

Asia WGS AF: 0.193 AC: 668 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.6
DANN	Benign	0.35
PhyloP100		0.59
Mutation Taster		=99/1	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: rs3748989; hg19: chr2-1946968; COSMIC: COSV67722525;