19-45768180-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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 (★).

• 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

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39808762).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX5	NM_175875.5	c.665G>C	p.Gly222Ala	missense_variant	Exon 1 of 3	ENST00000317578.7	NP_787071.3
DM1-AS	NR_147193.1	n.336+49C>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIX5	ENST00000317578.7	c.665G>C	p.Gly222Ala	missense_variant	Exon 1 of 3	1	NM_175875.5	ENSP00000316842.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Branchiootorenal syndrome 2 Uncertain:1

Feb 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

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;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;T
MetaSVM	Uncertain	-0.025	T
MutationAssessor	Benign	-1.0	N;N
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;P
Vest4		0.27
MutPred		0.30		Loss of methylation at R221 (P = 0.0891);Loss of methylation at R221 (P = 0.0891);
MVP		0.92
MPC		1.9
ClinPred		0.69	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.16
gMVP		0.51

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: rs1600400138; hg19: chr19-46271438;