19-45768177-T-C

Variant names:

• chr19-45768177-T-C
• rs776155687
• NM_175875.5:c.668A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_175875.5(SIX5):​c.668A>G​(p.Asn223Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SIX5 NM_175875.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.32
• Publications: 1 publications found

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]

ENSG00000259605 (HGNC:):

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175875.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX5	NM_175875.5	MANE Select	c.668A>G	p.Asn223Ser	missense	Exon 1 of 3	NP_787071.3
	DM1-AS	NR_147193.1		n.336+46T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX5	ENST00000317578.7	TSL:1 MANE Select	c.668A>G	p.Asn223Ser	missense	Exon 1 of 3	ENSP00000316842.4	Q8N196
	SIX5	ENST00000560160.1	TSL:2	c.449A>G	p.Asn150Ser	missense	Exon 1 of 2	ENSP00000453239.2	H0YLK1
	SIX5	ENST00000560168.1	TSL:4	c.131-65A>G		intron	N/A	ENSP00000453189.2	H0YLF6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 246702 AF XY: 0.00000745

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000903

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460574 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726664

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111752

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Branchiootorenal syndrome 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.8	L
PhyloP100		1.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.014	D
Polyphen		0.99	D
Vest4		0.48
MutPred		0.54		Gain of phosphorylation at N223 (P = 0.005)
MVP		0.94
MPC		1.3
ClinPred		0.98	D
GERP RS		4.5
PromoterAI		0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.65
gMVP		0.74
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs776155687; hg19: chr19-46271435;