Genetic Variant NM_201599.3:c.3803-4A>G (chrX-71241348-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_201599.3(ZMYM3):c.3803-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00095 in 1,173,233 control chromosomes in the GnomAD database, including 6 homozygotes. There are 263 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0052 ( 2 hom., 121 hem., cov: 22)

Exomes 𝑓: 0.00051 ( 4 hom. 142 hem. )

Consequence

ZMYM3
NM_201599.3 splice_region, intron

Scores

Splicing: ADA: 0.00002394

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -2.21

Publications

0 publications found

Variant links:

Genes affected

ZMYM3 (HGNC:13054): (zinc finger MYM-type containing 3) This gene is located on the X chromosome and is subject to X inactivation. It is highly conserved in vertebrates and most abundantly expressed in the brain. The encoded protein is a component of histone deacetylase-containing multiprotein complexes that function through modifying chromatin structure to keep genes silent. A chromosomal translocation (X;13) involving this gene is associated with X-linked cognitive disability. Several alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2010]

ZMYM3 Gene-Disease associations (from GenCC):

intellectual developmental disorder, X-linked 112
Inheritance: XL Classification: MODERATE Submitted by: G2P
intellectual disability
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics
syndromic intellectual disability
Inheritance: XL Classification: NO_KNOWN Submitted by: Illumina

ZMYM3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant X-71241348-T-C is Benign according to our data. Variant chrX-71241348-T-C is described in ClinVar as Benign. ClinVar VariationId is 711143.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00519 (575/110825) while in subpopulation AFR AF = 0.0183 (556/30417). AF 95% confidence interval is 0.017. There are 2 homozygotes in GnomAd4. There are 121 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201599.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ZMYM3	NM_201599.3	MANE Select	c.3803-4A>G	splice_region intron	N/A	NP_963893.1	Q14202-1
ZMYM3	NM_005096.3		c.3803-4A>G	splice_region intron	N/A	NP_005087.1	Q14202-1
ZMYM3	NM_001171162.1		c.3767-4A>G	splice_region intron	N/A	NP_001164633.1	Q14202-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ZMYM3	ENST00000314425.9	TSL:1 MANE Select	c.3803-4A>G	splice_region intron	N/A	ENSP00000322845.5	Q14202-1
ZMYM3	ENST00000373998.5	TSL:1	c.3767-4A>G	splice_region intron	N/A	ENSP00000363110.1	Q14202-2
ZMYM3	ENST00000373988.5	TSL:5	c.3809-4A>G	splice_region intron	N/A	ENSP00000363100.1	A6NHB5

Frequencies

GnomAD3 genomes

AF:

0.00519

AC:

575

AN:

110771

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0183

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00154

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00134

GnomAD2 exomes

AF:

0.00162

AC:

228

AN:

141168

AF XY:

0.00115

show subpopulations

Gnomad AFR exome

AF:

0.0201

Gnomad AMR exome

AF:

0.000268

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000165

Gnomad OTH exome

AF:

0.000555

GnomAD4 exome

AF:

0.000507

AC:

539

AN:

1062408

Hom.:

Cov.:

AF XY:

0.000425

AC XY:

142

AN XY:

333834

show subpopulations

African (AFR)

AF:

0.0182

AC:

467

AN:

25647

American (AMR)

AF:

0.000449

AC:

AN:

31215

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18171

East Asian (EAS)

AF:

0.00

AC:

AN:

29592

South Asian (SAS)

AF:

0.0000404

AC:

AN:

49483

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39233

Middle Eastern (MID)

AF:

0.000250

AC:

AN:

4001

European-Non Finnish (NFE)

AF:

0.0000134

AC:

AN:

820454

Other (OTH)

AF:

0.000986

AC:

AN:

44612

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00519

AC:

575

AN:

110825

Hom.:

Cov.:

AF XY:

0.00366

AC XY:

121

AN XY:

33037

show subpopulations

African (AFR)

AF:

0.0183

AC:

556

AN:

30417

American (AMR)

AF:

0.00154

AC:

AN:

10412

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3543

South Asian (SAS)

AF:

0.00

AC:

AN:

2543

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5932

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52920

Other (OTH)

AF:

0.00132

AC:

AN:

1512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00261

Hom.:

Bravo

AF:

0.00575

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

ZMYM3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.030

(source)

DANN

Benign

0.51

PhyloP100

-2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000024

dbscSNV1_RF

Benign

0.0040

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over