19-45765396-G-A

Position:

• chr19-45765396-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_175875.5(SIX5):​c.*105C>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 0.00795 in 1,523,012 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (121 hom.)
• Consequence: SIX5 NM_175875.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0180

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=-0.82).
• BP6: Variant 19-45765396-G-A is Benign according to our data. Variant chr19-45765396-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1318431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00663 (1010/152300) while in subpopulation SAS AF= 0.0221 (107/4832). AF 95% confidence interval is 0.0187. There are 9 homozygotes in gnomad4. There are 510 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1010 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIX5	NM_175875.5	c.*105C>T		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.*105C>T		3_prime_UTR_variant	3/3	1	NM_175875.5	ENSP00000316842	P1
	ENST00000559756.1	n.612G>A		non_coding_transcript_exon_variant	1/2	3
SIX5	ENST00000560160.1	c.*535C>T		3_prime_UTR_variant	2/2	2		ENSP00000453239
SIX5	ENST00000560168.1	c.*1751C>T		3_prime_UTR_variant	3/3	4		ENSP00000453189

Frequencies

GnomAD3 genomes AF: 0.00663 AC: 1009 AN: 152182 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0223

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00691

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.00809 AC: 11092 AN: 1370712 Hom.: 121 Cov.: 23 AF XY: 0.00862 AC XY: 5918 AN XY: 686606

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.0291

Gnomad4 ASJ exome AF: 0.00890

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.0248

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.00612

Gnomad4 OTH exome AF: 0.00768

GnomAD4 genome AF: 0.00663 AC: 1010 AN: 152300 Hom.: 9 Cov.: 33 AF XY: 0.00685 AC XY: 510 AN XY: 74468

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.0138

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0221

Gnomad4 FIN AF: 0.0121

Gnomad4 NFE AF: 0.00691

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00903 Hom.: 1

Bravo AF: 0.00606

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.7
DANN	Benign	0.64

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: rs117997878; hg19: chr19-46268654;