SIX5 p.Gly365Arg

Variant names:

• chr19-45766866-C-G
• NM_175875.5:c.1093G>C
• SIX5 p.Gly365Arg

Your query was ambiguous. Multiple possible variants found:

• chr19-45766866-C-G
• chr19-45766866-C-T
• chr19-45766864-CCC-ACG
• chr19-45766864-CCC-GCG
• chr19-45766864-CCC-TCG
• chr19-45766864-CCC-TCT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PS1 PM2 BP4_Moderate

The NM_175875.5(SIX5):​c.1093G>C​(p.Gly365Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SIX5 NM_175875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.465
• Publications: 0 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 4 ACMG points.

• PS1: Transcript NM_175875.5 (SIX5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23844045).

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.1093G>C	p.Gly365Arg	missense	Exon 2 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.1093G>C	p.Gly365Arg	missense	Exon 2 of 3	ENSP00000316842.4	Q8N196
	SIX5	ENST00000560168.1	TSL:4	c.*281G>C		3_prime_UTR	Exon 3 of 3	ENSP00000453189.2	H0YLF6
	SIX5	ENST00000560160.1	TSL:2	c.585-755G>C		intron	N/A	ENSP00000453239.2	H0YLK1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.47
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.96	N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.18	T
Varity_R		0.16
gMVP		0.32
Mutation Taster		=95/5	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-46270124;