rs869320713

Variant names:

• chr10-248370-G-A
• rs869320713
• NM_001370100.5:c.1262G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PP5_Moderate BP4

The NM_001370100.5(ZMYND11):​c.1262G>A​(p.Ser421Asn) 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 benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZMYND11 NM_001370100.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 9.65
• Publications: 2 publications found

Genes affected

ZMYND11 (HGNC:16966): (zinc finger MYND-type containing 11) The protein encoded by this gene was first identified by its ability to bind the adenovirus E1A protein. The protein localizes to the nucleus. It functions as a transcriptional repressor, and expression of E1A inhibits this repression. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ZMYND11 Gene-Disease associations (from GenCC):

• syndromic complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 30

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC107984190 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_001370100.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-248370-G-A is Pathogenic according to our data. Variant chr10-248370-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 225254.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3341695). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZMYND11	NM_001370100.5	c.1262G>A	p.Ser421Asn	missense_variant	Exon 13 of 15	ENST00000381604.9	NP_001357029.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZMYND11	ENST00000381604.9	c.1262G>A	p.Ser421Asn	missense_variant	Exon 13 of 15	5	NM_001370100.5	ENSP00000371017.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 30 Pathogenic:1

Apr 13, 2016

Tgen's Center for Rare Childhood Disorders, Translational Genomics Research Institute (tgen)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jan 19, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The S421N variant in the ZMYND11 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S421N variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S421N variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The S421N variant is a strong candidate for a pathogenic variant; however, the possibility it may be a rare benign variant cannot be excluded. -

Intellectual disability Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T;T;.;T;.;T;.;.;T;.;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;D;D;D;D;D;D;D;.;.;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.81	L;.;.;.;.;L;.;.;.;.;.;L;.
PhyloP100		9.6
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.53	N;.;N;.;N;N;N;.;N;.;N;N;.
REVEL	Benign	0.25
Sift	Benign	0.085	T;.;T;.;D;T;D;.;T;.;T;D;.
Sift4G	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.99, 0.97, 0.99	.;.;.;D;.;.;D;.;D;.;.;.;.
Vest4		0.60
MVP		0.21
MPC		1.6
ClinPred		0.82	D
GERP RS		5.9
Varity_R		0.37
gMVP		0.63
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs869320713; hg19: chr10-294310;