19-45765170-G-A

Position:

• chr19-45765170-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_175875.5(SIX5):​c.*331C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 450,142 control chromosomes in the GnomAD database, including 217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (172 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (45 hom.)
• Consequence: SIX5 NM_175875.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0980

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-45765170-G-A is Benign according to our data. Variant chr19-45765170-G-A is described in ClinVar as [Benign]. Clinvar id is 1271737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0888 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIX5	NM_175875.5	c.*331C>T		3_prime_UTR_variant	3/3	ENST00000317578.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIX5	ENST00000317578.7	c.*331C>T		3_prime_UTR_variant	3/3	1	NM_175875.5	P1
	ENST00000559756.1	n.386G>A		non_coding_transcript_exon_variant	1/2	3
SIX5	ENST00000560160.1	c.*761C>T		3_prime_UTR_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 3970 AN: 152218 Hom.: 171 Cov.: 33

Gnomad AFR AF: 0.0912

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00870

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0172

GnomAD4 exome AF: 0.00349 AC: 1039 AN: 297806 Hom.: 45 Cov.: 0 AF XY: 0.00301 AC XY: 472 AN XY: 156644

Gnomad4 AFR exome AF: 0.0953

Gnomad4 AMR exome AF: 0.00546

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000208

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000138

Gnomad4 OTH exome AF: 0.00417

GnomAD4 genome AF: 0.0262 AC: 3984 AN: 152336 Hom.: 172 Cov.: 33 AF XY: 0.0246 AC XY: 1836 AN XY: 74492

Gnomad4 AFR AF: 0.0913

Gnomad4 AMR AF: 0.00862

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0206 Hom.: 8

Bravo AF: 0.0301

Asia WGS AF: 0.00577 AC: 21 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.8
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs60009313; hg19: chr19-46268428;