chrX-47846275-C-T

Variant names:

• chrX-47846275-C-T
• rs183846665
• NM_007137.5:c.8C>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.8C>T​(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 1,207,460 control chromosomes in the GnomAD database, including 136 homozygotes. There are 6,115 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (13 hom., 344 hem., cov: 23)
  • Exomes 𝑓: 0.017 (123 hom. 5771 hem.)
• Consequence: ZNF81 NM_007137.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.245
• Publications: 7 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=0.0035823584).
• BP6: Variant X-47846275-C-T is Benign according to our data. Variant chrX-47846275-C-T is described in ClinVar as Benign. ClinVar VariationId is 130859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0117 (1309/112342) while in subpopulation NFE AF = 0.0187 (997/53230). AF 95% confidence interval is 0.0178. There are 13 homozygotes in GnomAd4. There are 344 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 XL,Unknown 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.8C>T	p.Ala3Val	missense	Exon 2 of 5	NP_009068.2	P51508
	ZNF81	NM_001378152.1		c.8C>T	p.Ala3Val	missense	Exon 3 of 6	NP_001365081.1	P51508
	ZNF81	NM_001378153.1		c.8C>T	p.Ala3Val	missense	Exon 2 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.8C>T	p.Ala3Val	missense	Exon 2 of 5	ENSP00000341151.7	P51508
	ZNF81	ENST00000334937.8	TSL:1	c.8C>T	p.Ala3Val	missense	Exon 3 of 4	ENSP00000334641.4	B1AJV1
	ZNF81	ENST00000376954.6	TSL:5	c.8C>T	p.Ala3Val	missense	Exon 3 of 6	ENSP00000366153.1	P51508

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1313 AN: 112290 Hom.: 14 Cov.: 23

Gnomad AFR AF: 0.00305

Gnomad AMI AF: 0.0425

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.00604

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00110

Gnomad FIN AF: 0.00323

Gnomad MID AF: 0.0210

Gnomad NFE AF: 0.0187

Gnomad OTH AF: 0.0112

GnomAD2 exomes AF: 0.00925 AC: 1607 AN: 173816 AF XY: 0.00854

Gnomad AFR exome AF: 0.00286

Gnomad AMR exome AF: 0.00574

Gnomad ASJ exome AF: 0.00589

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00294

Gnomad NFE exome AF: 0.0163

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.0166 AC: 18178 AN: 1095118 Hom.: 123 Cov.: 30 AF XY: 0.0160 AC XY: 5771 AN XY: 361160

African (AFR) AF: 0.00239 AC: 63 AN: 26363

American (AMR) AF: 0.00614 AC: 215 AN: 34996

Ashkenazi Jewish (ASJ) AF: 0.00574 AC: 111 AN: 19324

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30163

South Asian (SAS) AF: 0.00158 AC: 84 AN: 53328

European-Finnish (FIN) AF: 0.00343 AC: 138 AN: 40250

Middle Eastern (MID) AF: 0.00318 AC: 11 AN: 3454

European-Non Finnish (NFE) AF: 0.0201 AC: 16923 AN: 841296

Other (OTH) AF: 0.0138 AC: 632 AN: 45944

GnomAD4 genome AF: 0.0117 AC: 1309 AN: 112342 Hom.: 13 Cov.: 23 AF XY: 0.00997 AC XY: 344 AN XY: 34502

African (AFR) AF: 0.00304 AC: 94 AN: 30924

American (AMR) AF: 0.0124 AC: 132 AN: 10630

Ashkenazi Jewish (ASJ) AF: 0.00604 AC: 16 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3571

South Asian (SAS) AF: 0.00110 AC: 3 AN: 2716

European-Finnish (FIN) AF: 0.00323 AC: 20 AN: 6193

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.0187 AC: 997 AN: 53230

Other (OTH) AF: 0.0111 AC: 17 AN: 1532

Alfa AF: 0.0144 Hom.: 654

Bravo AF: 0.0120

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0208 AC: 60

ESP6500AA AF: 0.00260 AC: 9

ESP6500EA AF: 0.0200 AC: 130

ExAC AF: 0.00894 AC: 1081

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.043	T
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.24
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.027
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.036	D
Polyphen		0.32	B
Vest4		0.073
MVP		0.44
MPC		0.15
ClinPred		0.0037	T
GERP RS		2.7
Varity_R		0.11
gMVP		0.15
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs183846665; hg19: chrX-47705674; COSMIC: COSV99061323; COSMIC: COSV99061323;