chr19-45765548-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_175875.5(SIX5):​c.2173C>T​(p.Leu725=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000312 in 1,613,474 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00017 ( 2 hom. )

Consequence

SIX5
NM_175875.5 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.00
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 -16 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.51).
BP6
Variant 19-45765548-G-A is Benign according to our data. Variant chr19-45765548-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 512355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 253 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SIX5NM_175875.5 linkuse as main transcriptc.2173C>T p.Leu725= 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.2173C>T p.Leu725= synonymous_variant 3/31 NM_175875.5 ENSP00000316842 P1
ENST00000559756.1 linkuse as main transcriptn.764G>A non_coding_transcript_exon_variant 1/23
SIX5ENST00000560160.1 linkuse as main transcriptc.*383C>T 3_prime_UTR_variant 2/22 ENSP00000453239
SIX5ENST00000560168.1 linkuse as main transcriptc.*1599C>T 3_prime_UTR_variant 3/34 ENSP00000453189

Frequencies

GnomAD3 genomes
AF:
0.00162
AC:
247
AN:
152226
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00584
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.00
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000390
AC:
98
AN:
251196
Hom.:
0
AF XY:
0.000309
AC XY:
42
AN XY:
135878
show subpopulations
Gnomad AFR exome
AF:
0.00542
Gnomad AMR exome
AF:
0.000231
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000171
AC:
250
AN:
1461130
Hom.:
2
Cov.:
29
AF XY:
0.000161
AC XY:
117
AN XY:
726900
show subpopulations
Gnomad4 AFR exome
AF:
0.00562
Gnomad4 AMR exome
AF:
0.000224
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:
0.00000809
Gnomad4 OTH exome
AF:
0.000679
GnomAD4 genome
AF:
0.00166
AC:
253
AN:
152344
Hom.:
0
Cov.:
33
AF XY:
0.00179
AC XY:
133
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.00596
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000458
Hom.:
0
Bravo
AF:
0.00156
Asia WGS
AF:
0.00231
AC:
8
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 30, 2024- -
Likely benign, criteria provided, single submitterclinical testingGeneDxDec 15, 2020- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
not specified Benign:1
Likely benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of ChicagoAug 15, 2022- -
Branchiootorenal syndrome 2 Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsSep 06, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.51
CADD
Benign
18
DANN
Benign
0.90

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: rs112320524; hg19: chr19-46268806; API