X-47915014-A-G

Variant names:

• chrX-47915014-A-G
• rs1483423006
• NM_007137.5:c.368A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007137.5(ZNF81):​c.368A>G​(p.Asp123Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ZNF81 NM_007137.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0480

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031443715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF81	NM_007137.5	c.368A>G	p.Asp123Gly	missense_variant	Exon 5 of 5	ENST00000338637.13	NP_009068.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF81	ENST00000338637.13	c.368A>G	p.Asp123Gly	missense_variant	Exon 5 of 5	3	NM_007137.5	ENSP00000341151.7
ZNF81	ENST00000376954.6	c.368A>G	p.Asp123Gly	missense_variant	Exon 6 of 6	5		ENSP00000366153.1
ZNF81	ENST00000376950.4	c.277+19074A>G		intron_variant	Intron 4 of 4	5		ENSP00000366149.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.368A>G (p.D123G) alteration is located in exon 5 (coding exon 4) of the ZNF81 gene. This alteration results from a A to G substitution at nucleotide position 368, causing the aspartic acid (D) at amino acid position 123 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	9.1
DANN	Benign	0.55
DEOGEN2	Benign	0.020	T;T
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.10	.;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.031	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.070	N;N
REVEL	Benign	0.025
Sift	Benign	0.69	T;T
Sift4G	Benign	0.75	T;T
Polyphen		0.0	B;B
Vest4		0.089
MutPred		0.20		Loss of disorder (P = 0.1231);Loss of disorder (P = 0.1231);
MVP		0.43
MPC		0.20
ClinPred		0.039	T
GERP RS		0.40
Varity_R		0.13
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs1483423006; hg19: chrX-47774413;