chr19-45765548-G-C

Variant names:

• chr19-45765548-G-C
• rs112320524
• NM_175875.5:c.2173C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_175875.5(SIX5):​c.2173C>G​(p.Leu725Val) variant causes a missense change. 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.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SIX5 NM_175875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.00

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3670255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX5	NM_175875.5	c.2173C>G	p.Leu725Val	missense_variant	Exon 3 of 3	ENST00000317578.7	NP_787071.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIX5	ENST00000317578.7	c.2173C>G	p.Leu725Val	missense_variant	Exon 3 of 3	1	NM_175875.5	ENSP00000316842.4
SIX5	ENST00000560160	c.*383C>G		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000453239.2
SIX5	ENST00000560168	c.*1599C>G		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000453189.2
ENSG00000259605	ENST00000559756.1	n.764G>C		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.77	.;T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	0.69	N;N;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.84	.;N;.
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	.;D;D
Polyphen		1.0	D;D;.
Vest4		0.68, 0.60
MutPred		0.23		Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);.;
MVP		0.96
MPC		0.30
ClinPred		0.68	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.26

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: rs112320524; hg19: chr19-46268806;