19-45765195-C-T

Position:

• chr19-45765195-C-T

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.*306G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00847 in 510,016 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (114 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (41 hom.)
• Consequence: SIX5 NM_175875.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0910

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=-0.7).
• BP6: Variant 19-45765195-C-T is Benign according to our data. Variant chr19-45765195-C-T is described in ClinVar as [Benign]. Clinvar id is 1240611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0743 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIX5	NM_175875.5	c.*306G>A		3_prime_UTR_variant	3/3	ENST00000317578.7	NP_787071.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIX5	ENST00000317578.7	c.*306G>A		3_prime_UTR_variant	3/3	1	NM_175875.5	ENSP00000316842	P1
	ENST00000559756.1	n.411C>T		non_coding_transcript_exon_variant	1/2	3
SIX5	ENST00000560160.1	c.*736G>A		3_prime_UTR_variant	2/2	2		ENSP00000453239

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3304 AN: 152208 Hom.: 114 Cov.: 33

Gnomad AFR AF: 0.0765

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.00281 AC: 1006 AN: 357690 Hom.: 41 Cov.: 0 AF XY: 0.00246 AC XY: 464 AN XY: 188764

Gnomad4 AFR exome AF: 0.0783

Gnomad4 AMR exome AF: 0.00387

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000207

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000128

Gnomad4 OTH exome AF: 0.00425

GnomAD4 genome AF: 0.0217 AC: 3313 AN: 152326 Hom.: 114 Cov.: 33 AF XY: 0.0205 AC XY: 1527 AN XY: 74484

Gnomad4 AFR AF: 0.0765

Gnomad4 AMR AF: 0.00627

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0104 Hom.: 9

Bravo AF: 0.0254

Asia WGS AF: 0.00375 AC: 14 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.1
DANN	Benign	0.76
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: rs60934577; hg19: chr19-46268453;