Genetic Variant KIAA0825:p.Tyr857Phe (chr5-94417293-T-A) – 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_001145678.3(KIAA0825):c.2570A>T(p.Tyr857Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,550,684 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

KIAA0825
NM_001145678.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 1.72

Publications

0 publications found

Variant links:

Genes affected

KIAA0825 (HGNC:28532): (KIAA0825)

KIAA0825 Gene-Disease associations (from GenCC):

polydactyly, postaxial, type a10
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
postaxial polydactyly type A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KIAA0825 links:

Genome browser will be placed here

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=0.045664817).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145678.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIAA0825	NM_001145678.3	MANE Select	c.2570A>T	p.Tyr857Phe	missense	Exon 15 of 21	NP_001139150.1	A0A804HHT9
KIAA0825	NM_001385712.1		c.2585A>T	p.Tyr862Phe	missense	Exon 16 of 22	NP_001372641.1	A0A994J718
KIAA0825	NM_001388325.1		c.2585A>T	p.Tyr862Phe	missense	Exon 15 of 21	NP_001375254.1	A0A994J718

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIAA0825	ENST00000682413.1	MANE Select	c.2570A>T	p.Tyr857Phe	missense	Exon 15 of 21	ENSP00000506760.1	A0A804HHT9
KIAA0825	ENST00000504117.1	TSL:1	n.1432A>T		non_coding_transcript_exon	Exon 9 of 9
KIAA0825	ENST00000703867.1		c.2585A>T	p.Tyr862Phe	missense	Exon 15 of 21	ENSP00000515512.1	A0A994J718

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000832

AC:

AN:

156162

AF XY:

0.000109

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:

0.000216

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000622

AC:

AN:

1398598

Hom.:

Cov.:

AF XY:

0.0000522

AC XY:

AN XY:

689766

show subpopulations

African (AFR)

AF:

0.0000317

AC:

AN:

31572

American (AMR)

AF:

0.00

AC:

AN:

35698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25152

East Asian (EAS)

AF:

0.00

AC:

AN:

35656

South Asian (SAS)

AF:

0.00

AC:

AN:

79192

European-Finnish (FIN)

AF:

0.0000609

AC:

AN:

49256

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.0000742

AC:

AN:

1078418

Other (OTH)

AF:

0.0000518

AC:

AN:

57962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.0000526

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41420

American (AMR)

AF:

0.0000655

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.000158

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

KIAA0825-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.0093

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.82

M_CAP

Benign

0.0072

MetaRNN

Benign

0.046

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

PhyloP100

1.7

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.77

REVEL

Benign

0.069

Sift

Benign

0.68

Sift4G

Benign

0.60

Polyphen

0.0020

Vest4

0.20

MutPred

0.50

Gain of ubiquitination at K854 (P = 0.1084)

MVP

0.040

ClinPred

0.068

GERP RS

-0.0078

Varity_R

0.062

Mutation Taster

=94/6

polymorphism

(source)

Splicing

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