NM_007137.5:c.550C>G

Variant names:

• chrX-47915196-C-G
• rs113131552
• NM_007137.5:c.550C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_007137.5(ZNF81):​c.550C>G​(p.Leu184Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000259 in 1,202,595 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 79 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., 30 hem., cov: 23)
  • Exomes 𝑓: 0.00016 (0 hom. 49 hem.)
• Consequence: ZNF81 NM_007137.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.93
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041686893).
• BP6: Variant X-47915196-C-G is Benign according to our data. Variant chrX-47915196-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 590247.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 30 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.550C>G	p.Leu184Val	missense	Exon 5 of 5	NP_009068.2	P51508
	ZNF81	NM_001378152.1		c.550C>G	p.Leu184Val	missense	Exon 6 of 6	NP_001365081.1	P51508
	ZNF81	NM_001378153.1		c.550C>G	p.Leu184Val	missense	Exon 5 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.550C>G	p.Leu184Val	missense	Exon 5 of 5	ENSP00000341151.7	P51508
	ZNF81	ENST00000376954.6	TSL:5	c.550C>G	p.Leu184Val	missense	Exon 6 of 6	ENSP00000366153.1	P51508
	ZNF81	ENST00000853619.1		c.550C>G	p.Leu184Val	missense	Exon 5 of 5	ENSP00000523678.1

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 136 AN: 111796 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00419

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000381

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: 0.00200

GnomAD2 exomes AF: 0.000351 AC: 61 AN: 173901 AF XY: 0.000195

Gnomad AFR exome AF: 0.00417

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000127

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000160 AC: 174 AN: 1090747 Hom.: 0 Cov.: 31 AF XY: 0.000137 AC XY: 49 AN XY: 358317

African (AFR) AF: 0.00508 AC: 132 AN: 25974

American (AMR) AF: 0.000412 AC: 14 AN: 34000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19076

East Asian (EAS) AF: 0.00 AC: 0 AN: 30102

South Asian (SAS) AF: 0.00 AC: 0 AN: 52716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40351

Middle Eastern (MID) AF: 0.000735 AC: 3 AN: 4081

European-Non Finnish (NFE) AF: 0.00000715 AC: 6 AN: 838719

Other (OTH) AF: 0.000416 AC: 19 AN: 45728

GnomAD4 genome AF: 0.00122 AC: 137 AN: 111848 Hom.: 0 Cov.: 23 AF XY: 0.000881 AC XY: 30 AN XY: 34060

African (AFR) AF: 0.00421 AC: 130 AN: 30853

American (AMR) AF: 0.000381 AC: 4 AN: 10499

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.00 AC: 0 AN: 2691

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53150

Other (OTH) AF: 0.00197 AC: 3 AN: 1520

Alfa AF: 0.000215 Hom.: 3

Bravo AF: 0.00145

ESP6500AA AF: 0.00524 AC: 16

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000356 AC: 43

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	History of neurodevelopmental disorder (1)
-	-	1	ZNF81-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.33
DANN	Benign	0.78
DEOGEN2	Benign	0.027	T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.016	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.22	N
PhyloP100		-1.9
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.018
Sift	Benign	0.97	T
Sift4G	Benign	0.35	T
Polyphen		0.0080	B
Vest4		0.052
MVP		0.26
MPC		0.16
ClinPred		0.0065	T
GERP RS		-0.83
Varity_R		0.048
gMVP		0.022
Mutation Taster		=99/1	polymorphism

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: rs113131552; hg19: chrX-47774595;