Variant 19-45768192-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_175875.5(SIX5):c.653C>G(p.Ala218Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SIX5
NM_175875.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.09

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:

(HGNC:):

links:

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

DM1-AS links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIX5	NM_175875.5 linkuse as main transcript	c.653C>G	p.Ala218Gly	missense_variant	1/3	ENST00000317578.7	NP_787071.3
DM1-AS	NR_147193.1 linkuse as main transcript	n.336+61G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SIX5	ENST00000317578.7 linkuse as main transcript	c.653C>G	p.Ala218Gly	missense_variant	1/3	1	NM_175875.5	ENSP00000316842	P1
	ENST00000559756.1 linkuse as main transcript	n.1181-640G>C		intron_variant, non_coding_transcript_variant		3
DM1-AS	ENST00000590076.2 linkuse as main transcript	n.336+61G>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460762

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726736

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2023

The c.653C>G (p.A218G) alteration is located in exon 1 (coding exon 1) of the SIX5 gene. This alteration results from a C to G substitution at nucleotide position 653, causing the alanine (A) at amino acid position 218 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.90

.;D

M_CAP

Pathogenic

0.37

MetaRNN

Uncertain

0.68

D;D

MetaSVM

Uncertain

0.76

MutationAssessor

Benign

0.84

L;L

MutationTaster

Benign

1.0

D;N

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.62

.;N

REVEL

Uncertain

0.50

Sift

Uncertain

0.010

.;D

Sift4G

Uncertain

0.035

.;D

Polyphen

0.98

D;D

Vest4

0.27

MutPred

0.52

Loss of MoRF binding (P = 0.1258);Loss of MoRF binding (P = 0.1258);

MVP

0.97

MPC

2.0

ClinPred

0.90

GERP RS

4.5

Varity_R

0.34

gMVP

0.51

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over