Genetic Variant ZMYM5:p.Thr237Ile (chr13-19838862-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001142684.2(ZMYM5):c.710C>T(p.Thr237Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T237N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ZMYM5
NM_001142684.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.70

Publications

0 publications found

Variant links:

Genes affected

ZMYM5 (HGNC:13029): (zinc finger MYM-type containing 5) Predicted to enable zinc ion binding activity. Involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZMYM5 Gene-Disease associations (from GenCC):

multiple congenital anomalies/dysmorphic syndrome
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ZMYM5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10805896).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142684.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZMYM5	NM_001142684.2	MANE Select	c.710C>T	p.Thr237Ile	missense	Exon 5 of 8	NP_001136156.1	Q9UJ78-4
ZMYM5	NM_001039650.3		c.710C>T	p.Thr237Ile	missense	Exon 5 of 6	NP_001034739.1	Q9UJ78-1
ZMYM5	NM_001039649.3		c.587-1041C>T		intron	N/A	NP_001034738.1	Q9UJ78-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZMYM5	ENST00000337963.9	TSL:5 MANE Select	c.710C>T	p.Thr237Ile	missense	Exon 5 of 8	ENSP00000337034.4	Q9UJ78-4
ZMYM5	ENST00000382905.8	TSL:1	c.710C>T	p.Thr237Ile	missense	Exon 5 of 6	ENSP00000372361.4	Q9UJ78-1
ZMYM5	ENST00000382907.8	TSL:1	c.587-1041C>T		intron	N/A	ENSP00000372364.4	Q9UJ78-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727240

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

7.7

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.039

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.79

M_CAP

Benign

0.0099

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

1.7

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.037

Sift

Benign

0.060

Sift4G

Uncertain

0.039

Polyphen

0.0050

Vest4

0.18

MutPred

0.31

Gain of catalytic residue at P239 (P = 0.0297)

MVP

0.061

MPC

0.082

ClinPred

0.22

GERP RS

-0.40

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.043

gMVP

0.16

Mutation Taster

=94/6

polymorphism

(source)

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over