chr19-45765576-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_175875.5(SIX5):​c.2145C>T​(p.Asp715=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,613,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

SIX5
NM_175875.5 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -2.24
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
Variant 19-45765576-G-A is Benign according to our data. Variant chr19-45765576-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2150445.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=-2.24 with no splicing effect.
BS2
High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SIX5NM_175875.5 linkuse as main transcriptc.2145C>T p.Asp715= synonymous_variant 3/3 ENST00000317578.7 NP_787071.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SIX5ENST00000317578.7 linkuse as main transcriptc.2145C>T p.Asp715= synonymous_variant 3/31 NM_175875.5 ENSP00000316842 P1
ENST00000559756.1 linkuse as main transcriptn.792G>A non_coding_transcript_exon_variant 1/23
SIX5ENST00000560160.1 linkuse as main transcriptc.*355C>T 3_prime_UTR_variant 2/22 ENSP00000453239
SIX5ENST00000560168.1 linkuse as main transcriptc.*1571C>T 3_prime_UTR_variant 3/34 ENSP00000453189

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152178
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000864
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000797
AC:
20
AN:
250992
Hom.:
0
AF XY:
0.0000589
AC XY:
8
AN XY:
135816
show subpopulations
Gnomad AFR exome
AF:
0.0000617
Gnomad AMR exome
AF:
0.000202
Gnomad ASJ exome
AF:
0.000994
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000616
AC:
90
AN:
1461038
Hom.:
0
Cov.:
29
AF XY:
0.0000702
AC XY:
51
AN XY:
726862
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.000268
Gnomad4 ASJ exome
AF:
0.00111
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000342
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152296
Hom.:
0
Cov.:
33
AF XY:
0.0000537
AC XY:
4
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000864
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000823
Hom.:
0
Bravo
AF:
0.0000604
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

SIX5-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 23, 2022This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 17, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.84
CADD
Benign
0.0060
DANN
Benign
0.82
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs747106145; hg19: chr19-46268834; COSMIC: COSV52180139; COSMIC: COSV52180139; API