NM_175875.5:c.1655C>A

Variant names:

• chr19-45766066-G-T
• rs80356464
• NM_175875.5:c.1655C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_175875.5(SIX5):​c.1655C>A​(p.Thr552Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T552M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIX5 NM_175875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13
• Publications: 11 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]

SIX5 Gene-Disease associations (from GenCC):

• branchiootorenal syndrome 2

  Inheritance: Unknown, AD Classification: DEFINITIVE, LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• branchio-oto-renal syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: ClinGen, Orphanet

ENSG00000259605 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29563582).

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.1655C>A	p.Thr552Lys	missense	Exon 3 of 3	NP_787071.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX5	ENST00000317578.7	TSL:1 MANE Select	c.1655C>A	p.Thr552Lys	missense	Exon 3 of 3	ENSP00000316842.4	Q8N196
	SIX5	ENST00000560160.1	TSL:2	c.630C>A	p.Asp210Glu	missense	Exon 2 of 2	ENSP00000453239.2	H0YLK1
	SIX5	ENST00000560168.1	TSL:4	c.*1081C>A		3_prime_UTR	Exon 3 of 3	ENSP00000453189.2	H0YLF6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243278 AF XY: 0.00

Gnomad AFR exome AF: 0.0000638

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459698 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726038

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 85896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111258

Other (OTH) AF: 0.00 AC: 0 AN: 60318

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152140 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74314

African (AFR) AF: 0.0000241 AC: 1 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.0086	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.070
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.65	N
REVEL	Uncertain	0.51
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.012	D
Polyphen		0.80	P
Vest4		0.80
MutPred		0.66		Gain of ubiquitination at T552 (P = 0.0211)
MVP		0.89
MPC		0.33
ClinPred		0.32	T
GERP RS		4.4
Varity_R		0.13
gMVP		0.70
Mutation Taster		=42/58	disease causing

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: rs80356464; hg19: chr19-46269324;