NM_001190417.2:c.1136T>C

Variant names:

• chrX-46500438-A-G
• rs773799168
• NM_001190417.2:c.1136T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001190417.2(ZNF674):​c.1136T>C​(p.Ile379Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000638 in 1,097,815 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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: not found (cov: 23)
  • Exomes 𝑓: 0.0000064 (0 hom. 3 hem.)
• Consequence: ZNF674 NM_001190417.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.30
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05696541).
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF674	NM_001190417.2	c.1136T>C	p.Ile379Thr	missense_variant	Exon 6 of 6	ENST00000683375.1	NP_001177346.1
ZNF674	NM_001039891.3	c.1151T>C	p.Ile384Thr	missense_variant	Exon 6 of 6		NP_001034980.1
ZNF674	NM_001146291.2	c.1133T>C	p.Ile378Thr	missense_variant	Exon 6 of 6		NP_001139763.1
ZNF674	XM_011543943.4	c.1148T>C	p.Ile383Thr	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.1136T>C	p.Ile379Thr	missense_variant	Exon 6 of 6		NM_001190417.2	ENSP00000506769.1
ZNF674	ENST00000523374.5	c.1151T>C	p.Ile384Thr	missense_variant	Exon 6 of 6	1		ENSP00000429148.1
ZNF674	ENST00000414387.6	c.1133T>C	p.Ile378Thr	missense_variant	Exon 5 of 5	3		ENSP00000428248.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000165 AC: 3 AN: 181651 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000146

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.00000638 AC: 7 AN: 1097815 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 3 AN XY: 363259

African (AFR) AF: 0.00 AC: 0 AN: 26397

American (AMR) AF: 0.00 AC: 0 AN: 35204

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

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30197

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40502

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841783

Other (OTH) AF: 0.0000868 AC: 4 AN: 46070

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1151T>C (p.I384T) alteration is located in exon 6 (coding exon 4) of the ZNF674 gene. This alteration results from a T to C substitution at nucleotide position 1151, causing the isoleucine (I) at amino acid position 384 to be replaced by a threonine (T). 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	0.16
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.97
CADD	Benign	3.3
DANN	Benign	0.59
DEOGEN2	Benign	0.0056	T;.
FATHMM_MKL	Benign	0.000030	N
LIST_S2	Benign	0.25	T;T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.057	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.53	N;.
PhyloP100		3.3
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.6	N;N
REVEL	Benign	0.069
Sift	Uncertain	0.026	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		0.027	B;.
Vest4		0.027
MutPred		0.39		Loss of catalytic residue at I384 (P = 0.0221);.;
MVP		0.19
MPC		0.27
ClinPred		0.029	T
GERP RS		-1.0
Varity_R		0.046
gMVP		0.027
Mutation Taster		=88/12	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: rs773799168; hg19: chrX-46359873;