chr19-45765626-G-A

Position:

• chr19-45765626-G-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.2095C>T​(p.Pro699Ser) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P699P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SIX5 NM_175875.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37

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]

(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=0.15326324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIX5	NM_175875.5	c.2095C>T	p.Pro699Ser	missense_variant	3/3	ENST00000317578.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIX5	ENST00000317578.7	c.2095C>T	p.Pro699Ser	missense_variant	3/3	1	NM_175875.5	P1
	ENST00000559756.1	n.842G>A		non_coding_transcript_exon_variant	1/2	3
SIX5	ENST00000560160.1	c.*305C>T		3_prime_UTR_variant	2/2	2
SIX5	ENST00000560168.1	c.*1521C>T		3_prime_UTR_variant	3/3	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2023

The c.2095C>T (p.P699S) alteration is located in exon 3 (coding exon 3) of the SIX5 gene. This alteration results from a C to T substitution at nucleotide position 2095, causing the proline (P) at amino acid position 699 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.73	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.20	N;N;.
MutationTaster	Benign	0.70	D;D
PrimateAI	Uncertain	0.66	T
Polyphen		0.043	B;B;.
Vest4		0.31, 0.17
MutPred		0.23		Gain of phosphorylation at P699 (P = 0.0438);Gain of phosphorylation at P699 (P = 0.0438);.;
MVP		0.83
MPC		0.069
ClinPred		0.25	T
GERP RS		1.8
Varity_R		0.034
gMVP		0.35

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: chr19-46268884;