Genetic Variant NM_175875.5:c.2177C>G (chr19-45765544-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_175875.5(SIX5):c.2177C>G(p.Thr726Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,128 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SIX5
NM_175875.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 8.07

Variant links:

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]

SIX5 links:

ENSG00000259605 (HGNC:):

ENSG00000259605 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX5	NM_175875.5 link	c.2177C>G	p.Thr726Ser	missense_variant	Exon 3 of 3	ENST00000317578.7	NP_787071.3	Q8N196

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIX5	ENST00000317578.7 link	c.2177C>G	p.Thr726Ser	missense_variant	Exon 3 of 3	1	NM_175875.5	ENSP00000316842.4	Q8N196
SIX5	ENST00000560160 link	c.*387C>G		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000453239.2	H0YLK1
SIX5	ENST00000560168 link	c.*1603C>G		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000453189.2	H0YLF6
ENSG00000259605	ENST00000559756.1 link	n.760G>C		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251208

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726898

show subpopulations

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2177C>G (p.T726S) alteration is located in exon 3 (coding exon 3) of the SIX5 gene. This alteration results from a C to G substitution at nucleotide position 2177, causing the threonine (T) at amino acid position 726 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Branchiootorenal syndrome 2

Uncertain:1

Apr 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;T;T

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.66

.;T;T

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.52

D;D;D

MetaSVM

Uncertain

0.21

MutationAssessor

Benign

0.69

N;N;.

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.61

.;N;.

REVEL

Uncertain

0.47

Sift

Uncertain

0.0040

.;D;.

Sift4G

Uncertain

0.057

.;T;D

Polyphen

1.0

D;D;.

Vest4

0.58, 0.69

MutPred

0.20

Gain of phosphorylation at T726 (P = 0.0806);Gain of phosphorylation at T726 (P = 0.0806);.;

MVP

0.98

MPC

0.29

ClinPred

0.84

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over