X-135291061-C-G

Variant names:

• chrX-135291061-C-G
• NM_007131.5:c.771G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007131.5(ZNF75D):​c.771G>C​(p.Lys257Asn) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: ZNF75D NM_007131.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.146

Genes affected

ZNF75D (HGNC:13145): (zinc finger protein 75D) This gene encodes a protein that likely functions as a transcription factor. The protein, which belongs to the ZNF75 family, includes an N-terminal SCAN domain, a KRAB box, and five C2H2-type zinc finger motifs. Another functional gene belonging to this family is located on chromosome 16, while pseudogenes have been identified on chromosomes 11 and 12. Alternative splicing results in multiple transcripts variants. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25729573).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF75D	NM_007131.5	c.771G>C	p.Lys257Asn	missense_variant	Exon 6 of 7	ENST00000370766.8	NP_009062.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF75D	ENST00000370766.8	c.771G>C	p.Lys257Asn	missense_variant	Exon 6 of 7	1	NM_007131.5	ENSP00000359802.3
ZNF75D	ENST00000469456.1	n.543G>C		non_coding_transcript_exon_variant	Exon 1 of 2	1
ZNF75D	ENST00000370764.1	c.486G>C	p.Lys162Asn	missense_variant	Exon 3 of 4	2		ENSP00000359800.1
ZNF75D	ENST00000494295.1	n.828-35284G>C		intron_variant	Intron 1 of 3	2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.14e-7 AC: 1 AN: 1093706 Hom.: 0 Cov.: 28 AF XY: 0.00000278 AC XY: 1 AN XY: 359166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.771G>C (p.K257N) alteration is located in exon 5 (coding exon 4) of the ZNF75D gene. This alteration results from a G to C substitution at nucleotide position 771, causing the lysine (K) at amino acid position 257 to be replaced by an asparagine (N). 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	Pathogenic	0.93
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.
FATHMM_MKL	Benign	0.095	N
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.2	M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.067
Sift	Benign	0.032	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;.
Vest4		0.29
MutPred		0.57		Loss of ubiquitination at K257 (P = 0.0218);.;
MVP		0.45
MPC		0.63
ClinPred		0.95	D
GERP RS		1.9
Varity_R		0.31
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-134424987;