Genetic Variant NM_017908.4:c.983C>T (chr19-58480356-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_017908.4(ZNF446):c.983C>T(p.Pro328Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00777 in 1,603,316 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0046 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0081 ( 59 hom. )

Consequence

ZNF446
NM_017908.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.46

Publications

4 publications found

Variant links:

COSMIC-nc: COSV107428742

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044320524).

BP6

Variant 19-58480356-C-T is Benign according to our data. Variant chr19-58480356-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2650591.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

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.983C>T	p.Pro328Leu	missense	Exon 7 of 7	NP_060378.1	Q9NWS9-1
	ZNF446	NM_001304453.1		c.802+337C>T		intron	N/A	NP_001291382.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZNF446	ENST00000594369.6	TSL:1 MANE Select	c.983C>T	p.Pro328Leu	missense	Exon 7 of 7	ENSP00000472802.1	Q9NWS9-1
ZNF446	ENST00000610298.1	TSL:1	c.983C>T	p.Pro328Leu	missense	Exon 7 of 8	ENSP00000478778.1	Q9NWS9-2
ZNF446	ENST00000864814.1		c.983C>T	p.Pro328Leu	missense	Exon 6 of 6	ENSP00000534873.1

Frequencies

GnomAD3 genomes

AF:

0.00466

AC:

709

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00745

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00569

AC:

1290

AN:

226740

AF XY:

0.00612

show subpopulations

Gnomad AFR exome

AF:

0.00193

Gnomad AMR exome

AF:

0.00258

Gnomad ASJ exome

AF:

0.00413

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00263

Gnomad NFE exome

AF:

0.00888

Gnomad OTH exome

AF:

0.00605

GnomAD4 exome

AF:

0.00809

AC:

11745

AN:

1450980

Hom.:

Cov.:

AF XY:

0.00803

AC XY:

5788

AN XY:

720966

show subpopulations

African (AFR)

AF:

0.00165

AC:

AN:

33394

American (AMR)

AF:

0.00320

AC:

136

AN:

42476

Ashkenazi Jewish (ASJ)

AF:

0.00384

AC:

AN:

25792

East Asian (EAS)

AF:

0.0000509

AC:

AN:

39314

South Asian (SAS)

AF:

0.00544

AC:

462

AN:

84880

European-Finnish (FIN)

AF:

0.00246

AC:

127

AN:

51546

Middle Eastern (MID)

AF:

0.0117

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00934

AC:

10350

AN:

1107872

Other (OTH)

AF:

0.00746

AC:

447

AN:

59956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

814

1629

2443

3258

4072

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

390

780

1170

1560

1950

<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:

0.00465

AC:

708

AN:

152336

Hom.:

Cov.:

AF XY:

0.00426

AC XY:

317

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

41574

American (AMR)

AF:

0.00470

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00600

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00169

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00745

AC:

507

AN:

68020

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

101

135

169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00727

Hom.:

Bravo

AF:

0.00492

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00205

AC:

ESP6500EA

AF:

0.0101

AC:

ExAC

AF:

0.00563

AC:

682

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.62

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.073

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0044

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

-3.5

PrimateAI

Benign

0.33

Sift4G

Benign

0.48

Polyphen

0.0

Vest4

0.11

MVP

0.072

MPC

0.067

ClinPred

0.0027

GERP RS

-3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.042

gMVP

0.13

Mutation Taster

=99/1

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

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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