rs80356463

Variant names:

• chr19-45766866-C-A
• NM_175875.5:c.1093G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-45766866-C-A
• chr19-45766866-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_175875.5(SIX5):​c.1093G>T​(p.Gly365Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,392,246 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. G365R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SIX5 NM_175875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.465

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-45766866-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.3980856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX5	NM_175875.5	c.1093G>T	p.Gly365Trp	missense_variant	Exon 2 of 3	ENST00000317578.7	NP_787071.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIX5	ENST00000317578.7	c.1093G>T	p.Gly365Trp	missense_variant	Exon 2 of 3	1	NM_175875.5	ENSP00000316842.4
SIX5	ENST00000560168	c.*281G>T		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000453189.2
SIX5	ENST00000560160.1	c.585-755G>T		intron_variant	Intron 1 of 1	2		ENSP00000453239.2
ENSG00000259605	ENST00000559756.1	n.1180+902C>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1392246 Hom.: 0 Cov.: 34 AF XY: 0.00000146 AC XY: 1 AN XY: 686998

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.26e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.61	.;T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.40	T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.5	.;N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.014	.;D
Polyphen		0.99	D;D
Vest4		0.56
MutPred		0.46		Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);
MVP		0.79
MPC		0.31
ClinPred		0.61	D
GERP RS		0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-46270124;