chr19-45765456-C-T

Position:

• chr19-45765456-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.*45G>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 0.00504 in 1,612,082 control chromosomes in the GnomAD database, including 383 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (187 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (196 hom.)
• Consequence: SIX5 NM_175875.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.639

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=-0.8).
• BP6: Variant 19-45765456-C-T is Benign according to our data. Variant chr19-45765456-C-T is described in ClinVar as [Benign]. Clinvar id is 1251781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0931 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIX5	NM_175875.5	c.*45G>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.*45G>A		3_prime_UTR_variant	3/3	1	NM_175875.5	ENSP00000316842	P1
	ENST00000559756.1	n.672C>T		non_coding_transcript_exon_variant	1/2	3
SIX5	ENST00000560160.1	c.*475G>A		3_prime_UTR_variant	2/2	2		ENSP00000453239
SIX5	ENST00000560168.1	c.*1691G>A		3_prime_UTR_variant	3/3	4		ENSP00000453189

Frequencies

GnomAD3 genomes AF: 0.0272 AC: 4143 AN: 152148 Hom.: 186 Cov.: 33

Gnomad AFR AF: 0.0955

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.00723 AC: 1812 AN: 250782 Hom.: 86 AF XY: 0.00500 AC XY: 679 AN XY: 135746

Gnomad AFR exome AF: 0.0992

Gnomad AMR exome AF: 0.00466

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00272 AC: 3973 AN: 1459816 Hom.: 196 Cov.: 29 AF XY: 0.00229 AC XY: 1660 AN XY: 726268

Gnomad4 AFR exome AF: 0.0957

Gnomad4 AMR exome AF: 0.00505

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000155

Gnomad4 OTH exome AF: 0.00585

GnomAD4 genome AF: 0.0273 AC: 4157 AN: 152266 Hom.: 187 Cov.: 33 AF XY: 0.0261 AC XY: 1943 AN XY: 74452

Gnomad4 AFR AF: 0.0956

Gnomad4 AMR AF: 0.00797

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0128 Hom.: 19

Bravo AF: 0.0309

Asia WGS AF: 0.00722 AC: 26 AN: 3476

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	Jul 05, 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	-0.80
CADD	Benign	2.8
DANN	Benign	0.66

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: rs7257515; hg19: chr19-46268714;