NM_007137.5:c.129A>G

Variant names:

• chrX-47888073-A-G
• rs148626389
• NM_007137.5:c.129A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_007137.5(ZNF81):​c.129A>G​(p.Arg43Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,208,415 control chromosomes in the GnomAD database, including 11 homozygotes. There are 367 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (6 hom., 164 hem., cov: 22)
  • Exomes 𝑓: 0.00068 (5 hom. 203 hem.)
• Consequence: ZNF81 NM_007137.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.785
• Publications: 1 publications found

Genes affected

ZNF81 (HGNC:13156): (zinc finger protein 81) This gene encodes a protein that likely functions as a transcription factor. The protein contains an N-terminal KRAB domain and several C2H2-type zinc finger motifs. Mutations in this gene cause an X-linked form of intellectual disability (MRX45). Microduplication of a region of chromosome X including this gene has also been associated with other forms of intellectual disability. [provided by RefSeq, Jul 2017]

ZNF81 Gene-Disease associations (from GenCC):

• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability, X-linked 45

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• X-linked intellectual disability

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant X-47888073-A-G is Benign according to our data. Variant chrX-47888073-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 590232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.785 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00625 (691/110551) while in subpopulation AFR AF = 0.0218 (662/30363). AF 95% confidence interval is 0.0204. There are 6 homozygotes in GnomAd4. There are 164 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 Unknown,XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007137.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF81	NM_007137.5	MANE Select	c.129A>G	p.Arg43Arg	synonymous	Exon 3 of 5	NP_009068.2	P51508
	ZNF81	NM_001378152.1		c.129A>G	p.Arg43Arg	synonymous	Exon 4 of 6	NP_001365081.1	P51508
	ZNF81	NM_001378153.1		c.129A>G	p.Arg43Arg	synonymous	Exon 3 of 5	NP_001365082.1	P51508

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF81	ENST00000338637.13	TSL:3 MANE Select	c.129A>G	p.Arg43Arg	synonymous	Exon 3 of 5	ENSP00000341151.7	P51508
	ZNF81	ENST00000334937.8	TSL:1	c.129A>G	p.Arg43Arg	synonymous	Exon 4 of 4	ENSP00000334641.4	B1AJV1
	ZNF81	ENST00000376954.6	TSL:5	c.129A>G	p.Arg43Arg	synonymous	Exon 4 of 6	ENSP00000366153.1	P51508

Frequencies

GnomAD3 genomes AF: 0.00624 AC: 690 AN: 110502 Hom.: 6 Cov.: 22

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

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: 0.00

Gnomad OTH AF: 0.00405

GnomAD2 exomes AF: 0.00189 AC: 345 AN: 182310 AF XY: 0.00107

Gnomad AFR exome AF: 0.0232

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000369

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000676 AC: 742 AN: 1097864 Hom.: 5 Cov.: 31 AF XY: 0.000559 AC XY: 203 AN XY: 363258

African (AFR) AF: 0.0227 AC: 600 AN: 26401

American (AMR) AF: 0.00179 AC: 63 AN: 35144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30197

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4119

European-Non Finnish (NFE) AF: 0.0000190 AC: 16 AN: 841964

Other (OTH) AF: 0.00135 AC: 62 AN: 46077

GnomAD4 genome AF: 0.00625 AC: 691 AN: 110551 Hom.: 6 Cov.: 22 AF XY: 0.00500 AC XY: 164 AN XY: 32779

African (AFR) AF: 0.0218 AC: 662 AN: 30363

American (AMR) AF: 0.00221 AC: 23 AN: 10391

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2633

East Asian (EAS) AF: 0.00 AC: 0 AN: 3504

South Asian (SAS) AF: 0.00 AC: 0 AN: 2560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52840

Other (OTH) AF: 0.00400 AC: 6 AN: 1500

Alfa AF: 0.00330 Hom.: 14

Bravo AF: 0.00739

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	History of neurodevelopmental disorder (1)
-	-	1	not provided (1)
-	-	1	ZNF81-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.5
DANN	Benign	0.49
PhyloP100		-0.79
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: rs148626389; hg19: chrX-47747472;