19-45765818-G-T

Variant names:

• chr19-45765818-G-T
• NM_175875.5:c.1903C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_175875.5(SIX5):​c.1903C>A​(p.Pro635Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. P635S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SIX5 NM_175875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.360

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09326479).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX5	NM_175875.5	c.1903C>A	p.Pro635Thr	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.1903C>A	p.Pro635Thr	missense_variant	Exon 3 of 3	1	NM_175875.5	ENSP00000316842.4
SIX5	ENST00000560160	c.*113C>A		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000453239.2
SIX5	ENST00000560168	c.*1329C>A		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000453189.2
ENSG00000259605	ENST00000559756.1	n.1034G>T		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450114 Hom.: 0 Cov.: 82 AF XY: 0.00 AC XY: 0 AN XY: 721798

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.093	T;T;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.61	.;T;T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.093	T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.69	N;N;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.090	.;N;.
REVEL	Benign	0.23
Sift	Benign	0.27	.;T;.
Sift4G	Benign	0.58	.;T;D
Polyphen		0.0040	B;B;.
Vest4		0.084, 0.076
MutPred		0.27		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);.;
MVP		0.83
MPC		0.048
ClinPred		0.051	T
GERP RS		-0.76
Varity_R		0.048
gMVP		0.20

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: chr19-46269076;