19-45765469-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_175875.5(SIX5):c.*32T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00072 in 1,612,812 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0039 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (3 hom.)
• Consequence: SIX5 NM_175875.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0150

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 19-45765469-A-G is Benign according to our data. Variant chr19-45765469-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1317909.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 590 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIX5	NM_175875.5	c.*32T>C		3_prime_UTR_variant	3/3	ENST00000317578.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIX5	ENST00000317578.7	c.*32T>C		3_prime_UTR_variant	3/3	1	NM_175875.5	P1
	ENST00000559756.1	n.685A>G		non_coding_transcript_exon_variant	1/2	3
SIX5	ENST00000560160.1	c.*462T>C		3_prime_UTR_variant	2/2	2
SIX5	ENST00000560168.1	c.*1678T>C		3_prime_UTR_variant	3/3	4

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 590 AN: 152124 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000896 AC: 225 AN: 251074 Hom.: 1 AF XY: 0.000633 AC XY: 86 AN XY: 135826

Gnomad AFR exome AF: 0.0128

Gnomad AMR exome AF: 0.000289

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: 0.0000264

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000389 AC: 568 AN: 1460570 Hom.: 3 Cov.: 29 AF XY: 0.000361 AC XY: 262 AN XY: 726614

Gnomad4 AFR exome AF: 0.0144

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000845

GnomAD4 genome AF: 0.00390 AC: 594 AN: 152242 Hom.: 6 Cov.: 33 AF XY: 0.00375 AC XY: 279 AN XY: 74448

Gnomad4 AFR AF: 0.0134

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000783 Hom.: 0

Bravo AF: 0.00437

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	12
Dann	Benign	0.68

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: rs75443440; hg19: chr19-46268727;