chrX-46500459-C-T

Variant names:

• chrX-46500459-C-T
• rs1941398006
• NM_001190417.2:c.1115G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001190417.2(ZNF674):​c.1115G>A​(p.Arg372Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 112,604 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.40

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08948159).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF674	NM_001190417.2	c.1115G>A	p.Arg372Lys	missense_variant	Exon 6 of 6	ENST00000683375.1	NP_001177346.1
ZNF674	NM_001039891.3	c.1130G>A	p.Arg377Lys	missense_variant	Exon 6 of 6		NP_001034980.1
ZNF674	NM_001146291.2	c.1112G>A	p.Arg371Lys	missense_variant	Exon 6 of 6		NP_001139763.1
ZNF674	XM_011543943.4	c.1127G>A	p.Arg376Lys	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.1115G>A	p.Arg372Lys	missense_variant	Exon 6 of 6		NM_001190417.2	ENSP00000506769.1
ZNF674	ENST00000523374.5	c.1130G>A	p.Arg377Lys	missense_variant	Exon 6 of 6	1		ENSP00000429148.1
ZNF674	ENST00000414387.6	c.1112G>A	p.Arg371Lys	missense_variant	Exon 5 of 5	3		ENSP00000428248.1

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112604 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000645

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1097882 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363324

African (AFR) AF: 0.0000379 AC: 1 AN: 26396

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.00 AC: 0 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841835

Other (OTH) AF: 0.00 AC: 0 AN: 46073

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112604 Hom.: 0 Cov.: 24 AF XY: 0.0000288 AC XY: 1 AN XY: 34752

African (AFR) AF: 0.0000645 AC: 2 AN: 31006

American (AMR) AF: 0.00 AC: 0 AN: 10626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3589

South Asian (SAS) AF: 0.00 AC: 0 AN: 2759

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53391

Other (OTH) AF: 0.00 AC: 0 AN: 1516

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1130G>A (p.R377K) alteration is located in exon 6 (coding exon 4) of the ZNF674 gene. This alteration results from a G to A substitution at nucleotide position 1130, causing the arginine (R) at amino acid position 377 to be replaced by a lysine (K). 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	0.12
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.38
DANN	Benign	0.61
DEOGEN2	Benign	0.021	T;.
FATHMM_MKL	Benign	0.000060	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.00087	T
MetaRNN	Benign	0.089	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L;.
PhyloP100		-3.4
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.0030
Sift	Benign	0.11	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.0010	B;.
Vest4		0.058
MutPred		0.39		Gain of methylation at R377 (P = 0.0071);.;
MVP		0.30
MPC		0.21
ClinPred		0.10	T
GERP RS		-4.5
Varity_R		0.081
gMVP		0.062
Mutation Taster		=98/2	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

Publications

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Other links and lift over

dbSNP: rs1941398006; hg19: chrX-46359894;