rs769547318

Variant names:

• chrX-46500346-A-C
• rs769547318
• NM_001190417.2:c.1228T>G

Your query was ambiguous. Multiple possible variants found:

• chrX-46500346-A-C
• chrX-46500346-A-G
• chrX-46500346-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001190417.2(ZNF674):​c.1228T>G​(p.Cys410Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,772 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C410S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.16
• Publications: 0 publications found

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]

ZNF674 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: XL Classification: NO_KNOWN Submitted by: Ambry Genetics
• X-linked intellectual disability

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF674	NM_001190417.2	c.1228T>G	p.Cys410Gly	missense_variant	Exon 6 of 6	ENST00000683375.1	NP_001177346.1
ZNF674	NM_001039891.3	c.1243T>G	p.Cys415Gly	missense_variant	Exon 6 of 6		NP_001034980.1
ZNF674	NM_001146291.2	c.1225T>G	p.Cys409Gly	missense_variant	Exon 6 of 6		NP_001139763.1
ZNF674	XM_011543943.4	c.1240T>G	p.Cys414Gly	missense_variant	Exon 6 of 6		XP_011542245.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF674	ENST00000683375.1	c.1228T>G	p.Cys410Gly	missense_variant	Exon 6 of 6		NM_001190417.2	ENSP00000506769.1
ZNF674	ENST00000523374.5	c.1243T>G	p.Cys415Gly	missense_variant	Exon 6 of 6	1		ENSP00000429148.1
ZNF674	ENST00000414387.6	c.1225T>G	p.Cys409Gly	missense_variant	Exon 5 of 5	3		ENSP00000428248.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097772 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363170

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000379 AC: 1 AN: 26397

American (AMR) AF: 0.00 AC: 0 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30196

South Asian (SAS) AF: 0.00 AC: 0 AN: 54141

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40471

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841780

Other (OTH) AF: 0.00 AC: 0 AN: 46076

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.33	T;.
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.16	T;T
M_CAP	Benign	0.0070	T
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	4.0	H;.
PhyloP100		8.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-11	D;D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.52
MutPred		0.65		Gain of glycosylation at S416 (P = 0.0619);.;
MVP		0.97
MPC		0.91
ClinPred		1.0	D
GERP RS		2.2
Varity_R		0.96
gMVP		0.44
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs769547318; hg19: chrX-46359781;