chrX-46500156-A-G

Variant names:

• chrX-46500156-A-G
• rs199992077
• NM_001190417.2:c.1418T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001190417.2(ZNF674):​c.1418T>C​(p.Phe473Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000256 in 1,209,951 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000026 (0 hom. 9 hem.)
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.39
• 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: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81
• BS2: High Hemizygotes in GnomAdExome4 at 9 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001190417.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF674	NM_001190417.2	MANE Select	c.1418T>C	p.Phe473Ser	missense	Exon 6 of 6	NP_001177346.1	A0A804HHU7
	ZNF674	NM_001039891.3		c.1433T>C	p.Phe478Ser	missense	Exon 6 of 6	NP_001034980.1	Q2M3X9-1
	ZNF674	NM_001146291.2		c.1415T>C	p.Phe472Ser	missense	Exon 6 of 6	NP_001139763.1	Q2M3X9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF674	ENST00000683375.1	MANE Select	c.1418T>C	p.Phe473Ser	missense	Exon 6 of 6	ENSP00000506769.1	A0A804HHU7
	ZNF674	ENST00000523374.5	TSL:1	c.1433T>C	p.Phe478Ser	missense	Exon 6 of 6	ENSP00000429148.1	Q2M3X9-1
	ZNF674	ENST00000878263.1		c.1418T>C	p.Phe473Ser	missense	Exon 6 of 6	ENSP00000548322.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111930 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000275 AC: 5 AN: 182053 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000264 AC: 29 AN: 1098021 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 9 AN XY: 363397

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30192

South Asian (SAS) AF: 0.00 AC: 0 AN: 54144

European-Finnish (FIN) AF: 0.0000741 AC: 3 AN: 40490

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

European-Non Finnish (NFE) AF: 0.0000297 AC: 25 AN: 841984

Other (OTH) AF: 0.0000217 AC: 1 AN: 46090

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111930 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34124

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

African (AFR) AF: 0.00 AC: 0 AN: 30769

American (AMR) AF: 0.00 AC: 0 AN: 10536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3586

South Asian (SAS) AF: 0.00 AC: 0 AN: 2710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6099

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53157

Other (OTH) AF: 0.00 AC: 0 AN: 1513

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000978 Hom.: 1

Bravo AF: 0.0000113

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0050	T
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.70		Gain of disorder (P = 0.035)
MVP		0.88
MPC		1.1
ClinPred		0.81	D
GERP RS		0.94
Varity_R		0.90
gMVP		0.32
Mutation Taster		=100/0	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: rs199992077; hg19: chrX-46359591;