rs186251256

Variant names:

• chrX-47915200-C-T
• rs186251256
• NM_007137.5:c.554C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007137.5(ZNF81):​c.554C>T​(p.Ser185Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,202,294 control chromosomes in the GnomAD database, including 79 homozygotes. There are 4,859 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (6 hom., 272 hem., cov: 22)
  • Exomes 𝑓: 0.013 (73 hom. 4587 hem.)
• Consequence: ZNF81 NM_007137.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.336
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005334437).
• BP6: Variant X-47915200-C-T is Benign according to our data. Variant chrX-47915200-C-T is described in ClinVar as Benign. ClinVar VariationId is 130857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0133 (14557/1090513) while in subpopulation NFE AF = 0.0157 (13207/838581). AF 95% confidence interval is 0.0155. There are 73 homozygotes in GnomAdExome4. There are 4587 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. 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.554C>T	p.Ser185Leu	missense	Exon 5 of 5	NP_009068.2	P51508
	ZNF81	NM_001378152.1		c.554C>T	p.Ser185Leu	missense	Exon 6 of 6	NP_001365081.1	P51508
	ZNF81	NM_001378153.1		c.554C>T	p.Ser185Leu	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.554C>T	p.Ser185Leu	missense	Exon 5 of 5	ENSP00000341151.7	P51508
	ZNF81	ENST00000376954.6	TSL:5	c.554C>T	p.Ser185Leu	missense	Exon 6 of 6	ENSP00000366153.1	P51508
	ZNF81	ENST00000853619.1		c.554C>T	p.Ser185Leu	missense	Exon 5 of 5	ENSP00000523678.1

Frequencies

GnomAD3 genomes AF: 0.00961 AC: 1074 AN: 111729 Hom.: 6 Cov.: 22

Gnomad AFR AF: 0.00250

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.00909

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00149

Gnomad FIN AF: 0.00399

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.0181

GnomAD2 exomes AF: 0.00853 AC: 1484 AN: 174025 AF XY: 0.00849

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.00491

Gnomad ASJ exome AF: 0.00950

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00693

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.00973

GnomAD4 exome AF: 0.0133 AC: 14557 AN: 1090513 Hom.: 73 Cov.: 31 AF XY: 0.0128 AC XY: 4587 AN XY: 358101

African (AFR) AF: 0.00189 AC: 49 AN: 25972

American (AMR) AF: 0.00556 AC: 189 AN: 33973

Ashkenazi Jewish (ASJ) AF: 0.0106 AC: 202 AN: 19076

East Asian (EAS) AF: 0.00 AC: 0 AN: 30096

South Asian (SAS) AF: 0.00178 AC: 94 AN: 52685

European-Finnish (FIN) AF: 0.00748 AC: 302 AN: 40353

Middle Eastern (MID) AF: 0.00343 AC: 14 AN: 4080

European-Non Finnish (NFE) AF: 0.0157 AC: 13207 AN: 838581

Other (OTH) AF: 0.0109 AC: 500 AN: 45697

GnomAD4 genome AF: 0.00960 AC: 1073 AN: 111781 Hom.: 6 Cov.: 22 AF XY: 0.00800 AC XY: 272 AN XY: 33985

African (AFR) AF: 0.00250 AC: 77 AN: 30842

American (AMR) AF: 0.00981 AC: 103 AN: 10496

Ashkenazi Jewish (ASJ) AF: 0.00909 AC: 24 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3560

South Asian (SAS) AF: 0.00149 AC: 4 AN: 2685

European-Finnish (FIN) AF: 0.00399 AC: 24 AN: 6017

Middle Eastern (MID) AF: 0.00457 AC: 1 AN: 219

European-Non Finnish (NFE) AF: 0.0153 AC: 813 AN: 53124

Other (OTH) AF: 0.0178 AC: 27 AN: 1514

Alfa AF: 0.0124 Hom.: 597

Bravo AF: 0.00994

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0180 AC: 52

ESP6500AA AF: 0.00262 AC: 8

ESP6500EA AF: 0.0164 AC: 104

ExAC AF: 0.00881 AC: 1064

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.34
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.030
Sift	Benign	0.072	T
Sift4G	Benign	0.094	T
Polyphen		0.029	B
Vest4		0.072
MVP		0.40
MPC		0.14
ClinPred		0.011	T
GERP RS		3.2
Varity_R		0.22
gMVP		0.15
Mutation Taster		=98/2	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: rs186251256; hg19: chrX-47774599; COSMIC: COSV99061334;