NM_175875.5:c.665G>C

Variant names:

• chr19-45768180-C-G
• rs1600400138
• NM_175875.5:c.665G>C

Variant summary

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

The NM_175875.5(SIX5):​c.665G>C​(p.Gly222Ala) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G222D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SIX5 NM_175875.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.381
• 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]

ENSG00000259605 (HGNC:):

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

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=0.39808762).

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.665G>C	p.Gly222Ala	missense	Exon 1 of 3	NP_787071.3
	DM1-AS	NR_147193.1		n.336+49C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX5	ENST00000317578.7	TSL:1 MANE Select	c.665G>C	p.Gly222Ala	missense	Exon 1 of 3	ENSP00000316842.4	Q8N196
	SIX5	ENST00000560160.1	TSL:2	c.446G>C	p.Gly149Ala	missense	Exon 1 of 2	ENSP00000453239.2	H0YLK1
	SIX5	ENST00000560168.1	TSL:4	c.131-68G>C		intron	N/A	ENSP00000453189.2	H0YLF6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Branchiootorenal syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.094
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	-0.025	T
MutationAssessor	Benign	-1.0	N
PhyloP100		0.38
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.29
Sift	Benign	0.17	T
Sift4G	Benign	0.34	T
Polyphen		0.79	P
Vest4		0.27
MutPred		0.30		Loss of methylation at R221 (P = 0.0891)
MVP		0.92
MPC		1.9
ClinPred		0.69	D
GERP RS		4.4
PromoterAI		0.0036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.16
gMVP		0.51
Mutation Taster		=83/17	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: rs1600400138; hg19: chr19-46271438;