Genetic Variant NM_017908.4:c.719C>T (chr19-58479936-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017908.4(ZNF446):c.719C>T(p.Pro240Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000159 in 1,576,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

ZNF446
NM_017908.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.594

Publications

0 publications found

Variant links:

Genes affected

ZNF446 (HGNC:21036): (zinc finger protein 446) Enables identical protein binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ZNF446 links:

SLC27A5 (HGNC:10999): (solute carrier family 27 member 5) The protein encoded by this gene is an isozyme of very long-chain acyl-CoA synthetase (VLCS). It is capable of activating very long-chain fatty-acids containing 24- and 26-carbons. It is expressed in liver and associated with endoplasmic reticulum but not with peroxisomes. Its primary role is in fatty acid elongation or complex lipid synthesis rather than in degradation. This gene has a mouse ortholog. [provided by RefSeq, Jul 2008]

SLC27A5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.045820534).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017908.4. 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
	ZNF446	NM_017908.4	MANE Select	c.719C>T	p.Pro240Leu	missense	Exon 6 of 7	NP_060378.1	Q9NWS9-1
	ZNF446	NM_001304453.1		c.719C>T	p.Pro240Leu	missense	Exon 5 of 6	NP_001291382.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZNF446	ENST00000594369.6	TSL:1 MANE Select	c.719C>T	p.Pro240Leu	missense	Exon 6 of 7	ENSP00000472802.1	Q9NWS9-1
ZNF446	ENST00000610298.1	TSL:1	c.719C>T	p.Pro240Leu	missense	Exon 6 of 8	ENSP00000478778.1	Q9NWS9-2
ZNF446	ENST00000864814.1		c.719C>T	p.Pro240Leu	missense	Exon 5 of 6	ENSP00000534873.1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000208

AC:

AN:

191886

AF XY:

0.0000192

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000699

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000238

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000133

AC:

AN:

1424340

Hom.:

Cov.:

AF XY:

0.00000992

AC XY:

AN XY:

705756

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32876

American (AMR)

AF:

0.0000761

AC:

AN:

39418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25378

East Asian (EAS)

AF:

0.00

AC:

AN:

38018

South Asian (SAS)

AF:

0.0000245

AC:

AN:

81558

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45900

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.0000100

AC:

AN:

1096290

Other (OTH)

AF:

0.0000338

AC:

AN:

59174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000394

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41434

American (AMR)

AF:

0.000262

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2092

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

Genome Het

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:

0.000110

ExAC

AF:

0.00000833

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.067

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.099

LIST_S2

Benign

0.22

M_CAP

Benign

0.025

MetaRNN

Benign

0.046

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

0.59

PrimateAI

Benign

0.41

Sift4G

Uncertain

0.014

Polyphen

0.80

Vest4

0.23

MutPred

0.42

Gain of loop (P = 0.0079)

MVP

0.31

MPC

0.35

ClinPred

0.57

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.071

gMVP

0.25

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over