Genetic Variant SIX5:p.Ala218Val (chr19-45768192-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_175875.5(SIX5):c.653C>T(p.Ala218Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A218G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SIX5
NM_175875.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.09

Publications

0 publications found

Variant links:

Genes affected

SIX5 (HGNC:10891): (SIX homeobox 5) The protein encoded by this gene is a homeodomain-containing transcription factor that appears to function in the regulation of organogenesis. This gene is located downstream of the dystrophia myotonica-protein kinase gene. Mutations in this gene are a cause of branchiootorenal syndrome type 2. [provided by RefSeq, Jul 2009]

SIX5 links:

ENSG00000259605 (HGNC:):

ENSG00000259605 links:

DM1-AS (HGNC:53125): (DM1 locus antisense RNA)

DM1-AS links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.756

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175875.5. 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
	SIX5	NM_175875.5	MANE Select	c.653C>T	p.Ala218Val	missense	Exon 1 of 3	NP_787071.3
	DM1-AS	NR_147193.1		n.336+61G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIX5	ENST00000317578.7	TSL:1 MANE Select	c.653C>T	p.Ala218Val	missense	Exon 1 of 3	ENSP00000316842.4	Q8N196
SIX5	ENST00000560160.1	TSL:2	c.434C>T	p.Ala145Val	missense	Exon 1 of 2	ENSP00000453239.2	H0YLK1
SIX5	ENST00000560168.1	TSL:4	c.131-80C>T		intron	N/A	ENSP00000453189.2	H0YLF6

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000405

AC:

AN:

246980

AF XY:

0.00

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:

0.0000471

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460762

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726736

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52780

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111764

Other (OTH)

AF:

0.00

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

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:

0.00000656

AC:

AN:

152388

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74520

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41590

American (AMR)

AF:

0.00

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.76

MetaSVM

Pathogenic

0.91

MutationAssessor

Benign

1.2

PhyloP100

3.1

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.59

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.021

Polyphen

0.98

Vest4

0.31

MutPred

0.49

Gain of methylation at K217 (P = 0.0466)

MVP

0.97

MPC

2.0

ClinPred

0.76

GERP RS

4.5

PromoterAI

-0.13

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.35

gMVP

0.55

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over