X-135291105-A-G

Position:

• chrX-135291105-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007131.5(ZNF75D):​c.727T>C​(p.Tyr243His) 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: ZNF75D NM_007131.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.407

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28224498).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF75D	NM_007131.5	c.727T>C	p.Tyr243His	missense_variant	6/7	ENST00000370766.8	NP_009062.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF75D	ENST00000370766.8	c.727T>C	p.Tyr243His	missense_variant	6/7	1	NM_007131.5	ENSP00000359802	P2
ZNF75D	ENST00000469456.1	n.499T>C		non_coding_transcript_exon_variant	1/2	1
ZNF75D	ENST00000370764.1	c.442T>C	p.Tyr148His	missense_variant	3/4	2		ENSP00000359800	A2
ZNF75D	ENST00000494295.1	n.828-35328T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.727T>C (p.Y243H) alteration is located in exon 5 (coding exon 4) of the ZNF75D gene. This alteration results from a T to C substitution at nucleotide position 727, causing the tyrosine (Y) at amino acid position 243 to be replaced by a histidine (H). 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	0.33
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.92
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T;.
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.16	T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.8	D;N
REVEL	Benign	0.083
Sift	Benign	0.33	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.86	P;.
Vest4		0.14
MutPred		0.54		Gain of disorder (P = 0.074);.;
MVP		0.82
MPC		0.48
ClinPred		0.64	D
GERP RS		1.5
Varity_R		0.24
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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-134425031; COSMIC: COSV104425947;