rs2014576

Positions:

• chr19-45765818-G-A

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.1903C>T​(p.Pro635Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,602,080 control chromosomes in the GnomAD database, including 177,589 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15502 hom., cov: 32)
  • Exomes 𝑓: 0.47 (162087 hom.)
• Consequence: SIX5 NM_175875.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.360

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=7.834061E-6).
• BP6: Variant 19-45765818-G-A is Benign according to our data. Variant chr19-45765818-G-A is described in ClinVar as [Benign]. Clinvar id is 262912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45765818-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIX5	NM_175875.5	c.1903C>T	p.Pro635Ser	missense_variant	3/3	ENST00000317578.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIX5	ENST00000317578.7	c.1903C>T	p.Pro635Ser	missense_variant	3/3	1	NM_175875.5	P1
	ENST00000559756.1	n.1034G>A		non_coding_transcript_exon_variant	1/2	3
SIX5	ENST00000560160.1	c.*113C>T		3_prime_UTR_variant	2/2	2
SIX5	ENST00000560168.1	c.*1329C>T		3_prime_UTR_variant	3/3	4

Frequencies

GnomAD3 genomes AF: 0.443 AC: 67261 AN: 151912 Hom.: 15488 Cov.: 32

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.567

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.641

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.451

GnomAD3 exomes AF: 0.506 AC: 119863 AN: 237074 Hom.: 31561 AF XY: 0.503 AC XY: 65396 AN XY: 130078

Gnomad AFR exome AF: 0.344

Gnomad AMR exome AF: 0.670

Gnomad ASJ exome AF: 0.362

Gnomad EAS exome AF: 0.628

Gnomad SAS exome AF: 0.585

Gnomad FIN exome AF: 0.480

Gnomad NFE exome AF: 0.451

Gnomad OTH exome AF: 0.480

GnomAD4 exome AF: 0.467 AC: 677894 AN: 1450050 Hom.: 162087 Cov.: 82 AF XY: 0.470 AC XY: 339330 AN XY: 721764

Gnomad4 AFR exome AF: 0.343

Gnomad4 AMR exome AF: 0.657

Gnomad4 ASJ exome AF: 0.369

Gnomad4 EAS exome AF: 0.665

Gnomad4 SAS exome AF: 0.581

Gnomad4 FIN exome AF: 0.476

Gnomad4 NFE exome AF: 0.450

Gnomad4 OTH exome AF: 0.459

GnomAD4 genome AF: 0.443 AC: 67303 AN: 152030 Hom.: 15502 Cov.: 32 AF XY: 0.451 AC XY: 33489 AN XY: 74306

Gnomad4 AFR AF: 0.347

Gnomad4 AMR AF: 0.568

Gnomad4 ASJ AF: 0.370

Gnomad4 EAS AF: 0.641

Gnomad4 SAS AF: 0.586

Gnomad4 FIN AF: 0.466

Gnomad4 NFE AF: 0.450

Gnomad4 OTH AF: 0.454

Alfa AF: 0.441 Hom.: 5942

Bravo AF: 0.446

TwinsUK AF: 0.441 AC: 1635

ALSPAC AF: 0.455 AC: 1752

ESP6500AA AF: 0.345 AC: 1510

ESP6500EA AF: 0.433 AC: 3703

ExAC AF: 0.493 AC: 59560

Asia WGS AF: 0.586 AC: 2040 AN: 3478

EpiCase AF: 0.442

EpiControl AF: 0.440

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Branchiootorenal syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.080	T;T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.12	N
MetaRNN	Benign	0.0000078	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.49	T
Polyphen		0.0040	B;B;.
Vest4		0.057, 0.039
MPC		0.045
ClinPred		0.0043	T
GERP RS		-0.76
Varity_R		0.032
gMVP		0.18

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: rs2014576; hg19: chr19-46269076; COSMIC: COSV52175755; COSMIC: COSV52175755;