NM_001190417.2:c.975_976delCA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_001190417.2(ZNF674):c.975_976delCA(p.Ile326fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000504 in 1,209,643 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.000047 ( 0 hom. 16 hem. )

Consequence

ZNF674
NM_001190417.2 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.09

Publications

0 publications found

Variant links:

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

ZNF674 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant X-46500597-ATG-A is Benign according to our data. Variant chrX-46500597-ATG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228241.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF674	NM_001190417.2 link	c.975_976delCA	p.Ile326fs	frameshift_variant	Exon 6 of 6	ENST00000683375.1	NP_001177346.1	Q2M3X9A0A804HHU7
ZNF674	NM_001039891.3 link	c.990_991delCA	p.Ile331fs	frameshift_variant	Exon 6 of 6		NP_001034980.1	Q2M3X9-1
ZNF674	NM_001146291.2 link	c.972_973delCA	p.Ile325fs	frameshift_variant	Exon 6 of 6		NP_001139763.1	Q2M3X9-2
ZNF674	XM_011543943.4 link	c.987_988delCA	p.Ile330fs	frameshift_variant	Exon 6 of 6		XP_011542245.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF674	ENST00000683375.1 link	c.975_976delCA	p.Ile326fs	frameshift_variant	Exon 6 of 6		NM_001190417.2	ENSP00000506769.1	A0A804HHU7
ZNF674	ENST00000523374.5 link	c.990_991delCA	p.Ile331fs	frameshift_variant	Exon 6 of 6	1		ENSP00000429148.1	Q2M3X9-1
ZNF674	ENST00000414387.6 link	c.972_973delCA	p.Ile325fs	frameshift_variant	Exon 5 of 5	3		ENSP00000428248.1	Q2M3X9-2

Frequencies

GnomAD3 genomes

AF:

0.0000804

AC:

AN:

112004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

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:

0.000150

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000331

AC:

AN:

181530

AF XY:

0.0000594

show subpopulations

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:

0.0000740

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000474

AC:

AN:

1097639

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

363087

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26394

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.00

AC:

AN:

54137

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40495

Middle Eastern (MID)

AF:

0.00145

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000511

AC:

AN:

841625

Other (OTH)

AF:

0.0000651

AC:

AN:

46059

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000804

AC:

AN:

112004

Hom.:

Cov.:

AF XY:

0.0000877

AC XY:

AN XY:

34226

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30827

American (AMR)

AF:

0.00

AC:

AN:

10584

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3557

South Asian (SAS)

AF:

0.00

AC:

AN:

2699

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6096

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000150

AC:

AN:

53166

Other (OTH)

AF:

0.00

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000604

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 01, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 15, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ile331X (c.990_9901del) in exon 6 of ZNF674: This variant is not expected to h ave clinical significance because it has been identified in 0.4% (26/6239) of Eu ropean chromosomes by the NHLBI Exome Sequence Project (http://evs.gs.washington .edu/EVS). This variant is predicted to cause a frameshift, which alters the pro tein?s amino acid sequence beginning at position 331 and leads to an immediate p remature termination codon. This alteration occurs within the last exon and is m ore likely to escape nonsense mediated decay (NMD) and result in a truncated pro tein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

Mutation Taster

=182/18

polymorphism

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over