Genetic Variant SIX5:p.Gly365Trp (chr19-45766866-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_175875.5(SIX5):c.1093G>T(p.Gly365Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,392,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. G365R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

SIX5
NM_175875.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.465

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 Gene-Disease associations (from GenCC):

branchiootorenal syndrome 2
Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
branchio-oto-renal syndrome
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen

SIX5 links:

ENSG00000259605 (HGNC:):

ENSG00000259605 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-45766866-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 8600.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.3980856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX5	NM_175875.5 link	c.1093G>T	p.Gly365Trp	missense_variant	Exon 2 of 3	ENST00000317578.7	NP_787071.3	Q8N196

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIX5	ENST00000317578.7 link	c.1093G>T	p.Gly365Trp	missense_variant	Exon 2 of 3	1	NM_175875.5	ENSP00000316842.4	Q8N196
SIX5	ENST00000560168.1 link	c.*281G>T		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000453189.2	H0YLF6
SIX5	ENST00000560160.1 link	c.585-755G>T		intron_variant	Intron 1 of 1	2		ENSP00000453239.2	H0YLK1
ENSG00000259605	ENST00000559756.1 link	n.1180+902C>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.18e-7

AC:

AN:

1392246

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

686998

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31622

American (AMR)

AF:

0.00

AC:

AN:

36228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25102

East Asian (EAS)

AF:

0.00

AC:

AN:

35900

South Asian (SAS)

AF:

0.00

AC:

AN:

79592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41700

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4714

European-Non Finnish (NFE)

AF:

9.26e-7

AC:

AN:

1079606

Other (OTH)

AF:

0.00

AC:

AN:

57782

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

T;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.61

.;T

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.40

T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

0.55

N;N

PhyloP100

0.47

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.5

.;N

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.014

.;D

Polyphen

0.99

D;D

Vest4

0.56

MutPred

0.46

Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);

MVP

0.79

MPC

0.31

ClinPred

0.61

GERP RS

0.52

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.28

Mutation Taster

=97/3

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over