19-45768113-C-T

Position:

• chr19-45768113-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_175875.5(SIX5):​c.732G>A​(p.Gln244=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00377 in 1,607,614 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (15 hom.)
• Consequence: SIX5 NM_175875.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.64

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]

DM1-AS (HGNC:53125): (DM1 locus antisense RNA)

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.395247).
• BP6: Variant 19-45768113-C-T is Benign according to our data. Variant chr19-45768113-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 594586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45768113-C-T is described in Lovd as [Benign]. Variant chr19-45768113-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.64 with no splicing effect.
• BS2: High AC in GnomAd4 at 505 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIX5	NM_175875.5	c.732G>A	p.Gln244=	synonymous_variant	1/3	ENST00000317578.7
DM1-AS	NR_147193.1	n.318C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIX5	ENST00000317578.7	c.732G>A	p.Gln244=	synonymous_variant	1/3	1	NM_175875.5	P1
DM1-AS	ENST00000590076.2	n.318C>T		non_coding_transcript_exon_variant	1/2	4
	ENST00000559756.1	n.1181-719C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00332 AC: 505 AN: 152258 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00535

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00307 AC: 742 AN: 241644 Hom.: 3 AF XY: 0.00301 AC XY: 397 AN XY: 132060

Gnomad AFR exome AF: 0.000589

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.00426

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000328

Gnomad FIN exome AF: 0.000855

Gnomad NFE exome AF: 0.00448

Gnomad OTH exome AF: 0.00384

GnomAD4 exome AF: 0.00381 AC: 5549 AN: 1455238 Hom.: 15 Cov.: 31 AF XY: 0.00377 AC XY: 2729 AN XY: 723948

Gnomad4 AFR exome AF: 0.000808

Gnomad4 AMR exome AF: 0.00433

Gnomad4 ASJ exome AF: 0.00338

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.00103

Gnomad4 NFE exome AF: 0.00449

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00331 AC: 505 AN: 152376 Hom.: 2 Cov.: 33 AF XY: 0.00301 AC XY: 224 AN XY: 74504

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00535

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00354 Hom.: 0

Bravo AF: 0.00349

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00276 AC: 333

EpiCase AF: 0.00523

EpiControl AF: 0.00628

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	SIX5: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 20, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 02, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Uncertain	0.98
FATHMM_MKL	Uncertain	0.80	D
MutationTaster	Benign	1.0	D;N
GERP RS		3.7

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: rs141944211; hg19: chr19-46271371;