X-46500505-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001190417.2(ZNF674):c.1069C>A(p.His357Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,210,446 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 37 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., 6 hem., cov: 23)
  • Exomes 𝑓: 0.00012 (0 hom. 31 hem.)
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Benign/Likely benign no assertion criteria provided B:2
• Conservation: PhyloP100: 1.34

Genes affected

ZNF674 (HGNC:17625): (zinc finger protein 674) This gene encodes a zinc finger protein with an N-terminal Kruppel-associated box-containing (KRAB) domain and 11 Kruppel-type C2H2 zinc finger domains. Like other zinc finger proteins, this gene may function as a transcription factor. This gene resides on an area of chromosome X that has been implicated in nonsyndromic X-linked cognitive disabilities. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007669717).
• BP6: Variant X-46500505-G-T is Benign according to our data. Variant chrX-46500505-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1206390.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-46500505-G-T is described in Lovd as [Likely_benign]. Variant chrX-46500505-G-T is described in Lovd as [Benign].
• BS2: High Hemizygotes in GnomAd at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF674	NM_001190417.2	c.1069C>A	p.His357Asn	missense_variant	6/6	ENST00000683375.1
ZNF674	NM_001039891.3	c.1084C>A	p.His362Asn	missense_variant	6/6
ZNF674	NM_001146291.2	c.1066C>A	p.His356Asn	missense_variant	6/6
ZNF674	XM_011543943.4	c.1081C>A	p.His361Asn	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF674	ENST00000683375.1	c.1069C>A	p.His357Asn	missense_variant	6/6		NM_001190417.2	A1
ZNF674	ENST00000523374.5	c.1084C>A	p.His362Asn	missense_variant	6/6	1		P4
ZNF674	ENST00000414387.6	c.1066C>A	p.His356Asn	missense_variant	5/5	3		A1

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 20 AN: 112644 Hom.: 0 Cov.: 23 AF XY: 0.000172 AC XY: 6 AN XY: 34804

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000942

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000187

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000248 AC: 45 AN: 181159 Hom.: 1 AF XY: 0.000149 AC XY: 10 AN XY: 67119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00322

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000118 AC: 129 AN: 1097748 Hom.: 0 Cov.: 31 AF XY: 0.0000854 AC XY: 31 AN XY: 363182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00381

Gnomad4 SAS exome AF: 0.0000369

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000107

Gnomad4 OTH exome AF: 0.0000651

GnomAD4 genome AF: 0.000177 AC: 20 AN: 112698 Hom.: 0 Cov.: 23 AF XY: 0.000172 AC XY: 6 AN XY: 34868

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000941

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00502

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000187

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000378 Hom.: 5

Bravo AF: 0.000283

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000154 AC: 1

ExAC AF: 0.000273 AC: 33

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	9.6
Dann	Benign	0.64
DEOGEN2	Benign	0.015	T;.
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.18	T;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.0077	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.92	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.96	D;.
Vest4		0.20
MVP		0.34
MPC		0.51
ClinPred		0.050	T
GERP RS		-0.62
Varity_R		0.094
gMVP		0.025

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: rs180754888; hg19: chrX-46359940;