Genetic Variant NM_175875.5:c.1903C>A (chr19-45765818-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_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. 16/22 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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.360

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

branchiootorenal syndrome 2
Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
branchio-oto-renal syndrome
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen

SIX5 links:

ENSG00000259605 (HGNC:):

ENSG00000259605 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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 link	c.1903C>A	p.Pro635Thr	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.1903C>A	p.Pro635Thr	missense_variant	Exon 3 of 3	1	NM_175875.5	ENSP00000316842.4	Q8N196
ENSG00000259605	ENST00000559756.1 link	n.1034G>T		non_coding_transcript_exon_variant	Exon 1 of 2	3
SIX5	ENST00000560160.1 link	c.*113C>A		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000453239.2	H0YLK1
SIX5	ENST00000560168.1 link	c.*1329C>A		3_prime_UTR_variant	Exon 3 of 3	4		ENSP00000453189.2	H0YLF6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1450114

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721798

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111664

Other (OTH)

AF:

0.0000166

AC:

AN:

60300

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

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

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

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

LIST_S2

Benign

0.61

.;T;T

M_CAP

Benign

0.076

MetaRNN

Benign

0.093

T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.69

N;N;.

PhyloP100

0.36

PrimateAI

Uncertain

0.51

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

GERP RS

-0.76

Varity_R

0.048

gMVP

0.20

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over