rs2341097

chr19-45765644-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.2077G>A(p.Val693Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,612,970 control chromosomes in the GnomAD database, including 97,361 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8345 hom., cov: 33)
  • Exomes 𝑓: 0.35 (89016 hom.)
• Consequence: SIX5 NM_175875.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0790

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 (MetaRNN=0.0041387975).
• BP6: Variant 19-45765644-C-T is Benign according to our data. Variant chr19-45765644-C-T is described in ClinVar as [Benign]. Clinvar id is 262913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45765644-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIX5	NM_175875.5	c.2077G>A	p.Val693Met	missense_variant	3/3	ENST00000317578.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIX5	ENST00000317578.7	c.2077G>A	p.Val693Met	missense_variant	3/3	1	NM_175875.5	P1
	ENST00000559756.1	n.860C>T		non_coding_transcript_exon_variant	1/2	3
SIX5	ENST00000560160.1	c.*287G>A		3_prime_UTR_variant	2/2	2
SIX5	ENST00000560168.1	c.*1503G>A		3_prime_UTR_variant	3/3	4

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49969 AN: 151972 Hom.: 8344 Cov.: 33

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.319

GnomAD3 exomes AF: 0.320 AC: 79957 AN: 250156 Hom.: 13482 AF XY: 0.323 AC XY: 43820 AN XY: 135532

Gnomad AFR exome AF: 0.314

Gnomad AMR exome AF: 0.210

Gnomad ASJ exome AF: 0.424

Gnomad EAS exome AF: 0.284

Gnomad SAS exome AF: 0.290

Gnomad FIN exome AF: 0.319

Gnomad NFE exome AF: 0.357

Gnomad OTH exome AF: 0.338

GnomAD4 exome AF: 0.345 AC: 504731 AN: 1460880 Hom.: 89016 Cov.: 60 AF XY: 0.345 AC XY: 251012 AN XY: 726800

Gnomad4 AFR exome AF: 0.308

Gnomad4 AMR exome AF: 0.218

Gnomad4 ASJ exome AF: 0.418

Gnomad4 EAS exome AF: 0.218

Gnomad4 SAS exome AF: 0.293

Gnomad4 FIN exome AF: 0.314

Gnomad4 NFE exome AF: 0.360

Gnomad4 OTH exome AF: 0.350

GnomAD4 genome AF: 0.329 AC: 49984 AN: 152090 Hom.: 8345 Cov.: 33 AF XY: 0.323 AC XY: 24007 AN XY: 74368

Gnomad4 AFR AF: 0.313

Gnomad4 AMR AF: 0.262

Gnomad4 ASJ AF: 0.415

Gnomad4 EAS AF: 0.266

Gnomad4 SAS AF: 0.289

Gnomad4 FIN AF: 0.319

Gnomad4 NFE AF: 0.358

Gnomad4 OTH AF: 0.316

Alfa AF: 0.344 Hom.: 6193

Bravo AF: 0.323

TwinsUK AF: 0.362 AC: 1341

ALSPAC AF: 0.352 AC: 1355

ESP6500AA AF: 0.305 AC: 1342

ESP6500EA AF: 0.364 AC: 3127

ExAC AF: 0.319 AC: 38720

Asia WGS AF: 0.285 AC: 991 AN: 3478

EpiCase AF: 0.371

EpiControl AF: 0.375

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

Branchiootorenal syndrome 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.42	N
MetaRNN	Benign	0.0041	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.70	T
Polyphen		0.63	P;P;.
Vest4		0.27, 0.068
MPC		0.13
ClinPred		0.018	T
GERP RS		3.1
Varity_R		0.083
gMVP		0.067

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: rs2341097; hg19: chr19-46268902; COSMIC: COSV52177974; COSMIC: COSV52177974;