chrX-135287769-C-T

Variant names:

• chrX-135287769-C-T
• rs139971483
• NM_007131.5:c.901G>A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_007131.5(ZNF75D):​c.901G>A​(p.Glu301Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,208,466 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 41 hemizygotes in GnomAD. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 3 hem., cov: 24)
  • Exomes 𝑓: 0.00010 (0 hom. 38 hem.)
• Consequence: ZNF75D NM_007131.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.607

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031093001).
• BP6: Variant X-135287769-C-T is Benign according to our data. Variant chrX-135287769-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2380037.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-135287769-C-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF75D	NM_007131.5	c.901G>A	p.Glu301Lys	missense_variant	Exon 7 of 7	ENST00000370766.8	NP_009062.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF75D	ENST00000370766.8	c.901G>A	p.Glu301Lys	missense_variant	Exon 7 of 7	1	NM_007131.5	ENSP00000359802.3
ZNF75D	ENST00000469456.1	n.673G>A		non_coding_transcript_exon_variant	Exon 2 of 2	1
ZNF75D	ENST00000370764.1	c.616G>A	p.Glu206Lys	missense_variant	Exon 4 of 4	2		ENSP00000359800.1
ZNF75D	ENST00000494295.1	n.828-31992G>A		intron_variant	Intron 1 of 3	2

Frequencies

GnomAD3 genomes AF: 0.000205 AC: 23 AN: 112458 Hom.: 0 Cov.: 24 AF XY: 0.0000866 AC XY: 3 AN XY: 34640

Gnomad AFR AF: 0.000452

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000283

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000938

Gnomad OTH AF: 0.000658

GnomAD3 exomes AF: 0.000111 AC: 20 AN: 180924 Hom.: 0 AF XY: 0.000152 AC XY: 10 AN XY: 65680

Gnomad AFR exome AF: 0.000229

Gnomad AMR exome AF: 0.000149

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000160

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000103 AC: 113 AN: 1095952 Hom.: 0 Cov.: 31 AF XY: 0.000105 AC XY: 38 AN XY: 361504

Gnomad4 AFR exome AF: 0.0000761

Gnomad4 AMR exome AF: 0.000288

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000374

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000115

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.000204 AC: 23 AN: 112514 Hom.: 0 Cov.: 24 AF XY: 0.0000864 AC XY: 3 AN XY: 34706

Gnomad4 AFR AF: 0.000451

Gnomad4 AMR AF: 0.000282

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000938

Gnomad4 OTH AF: 0.000650

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000234

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

May 27, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.22
DANN	Benign	0.30
DEOGEN2	Benign	0.023	T;.
FATHMM_MKL	Benign	0.000020	N
LIST_S2	Benign	0.10	T;T
M_CAP	Benign	0.00053	T
MetaRNN	Benign	0.031	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.49	N;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.20	N;N
REVEL	Benign	0.0090
Sift	Benign	0.96	T;T
Sift4G	Benign	0.84	T;T
Polyphen		0.0	B;.
Vest4		0.038
MVP		0.58
MPC		0.14
ClinPred		0.017	T
GERP RS		-1.7
Varity_R		0.051
gMVP		0.17

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: rs139971483; hg19: chrX-134421701; COSMIC: COSV66133358;