Genetic Variant SIX4:p.Pro509Ser (chr14-60719784-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_017420.5(SIX4):c.1525C>T(p.Pro509Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

SIX4
NM_017420.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.38

Variant links:

Genes affected

SIX4 (HGNC:10890): (SIX homeobox 4) This gene encodes a member of the homeobox family, subfamily SIX. The drosophila homolog is a nuclear homeoprotein required for eye development. Studies in mouse show that this gene product functions as a transcription factor, and may have a role in the differentiation or maturation of neuronal cells. [provided by RefSeq, May 2010]

SIX4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009533852).

BS2

High AC in GnomAd4 at 82 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX4	NM_017420.5 link	c.1525C>T	p.Pro509Ser	missense_variant	Exon 2 of 3	ENST00000216513.5	NP_059116.3	Q9UIU6
SIX4	XM_005267759.3 link	c.1501C>T	p.Pro501Ser	missense_variant	Exon 3 of 4		XP_005267816.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SIX4	ENST00000216513.5 link	c.1525C>T	p.Pro509Ser	missense_variant	Exon 2 of 3	1	NM_017420.5	ENSP00000216513.4	Q9UIU6
SIX4	ENST00000554079.1 link	n.942C>T		non_coding_transcript_exon_variant	Exon 3 of 4	1
SIX4	ENST00000556952.3 link	c.*18C>T		downstream_gene_variant		5		ENSP00000450761.3	G3V2N2

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000175

AC:

AN:

251102

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135708

show subpopulations

Gnomad AFR exome

AF:

0.00240

Gnomad AMR exome

AF:

0.000145

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000650

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00212

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000538

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00181

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000993

Hom.:

Bravo

AF:

0.000570

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000206

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1525C>T (p.P509S) alteration is located in exon 2 (coding exon 2) of the SIX4 gene. This alteration results from a C to T substitution at nucleotide position 1525, causing the proline (P) at amino acid position 509 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

0.081

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.69

DEOGEN2

Benign

0.092

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.60

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.77

M_CAP

Benign

0.019

MetaRNN

Benign

0.0095

MetaSVM

Benign

-0.76

MutationAssessor

Benign

-0.14

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.3

REVEL

Benign

0.11

Sift

Benign

0.21

Sift4G

Benign

0.40

Polyphen

0.0

Vest4

0.12

MVP

0.27

MPC

0.086

ClinPred

0.0073

GERP RS

3.9

Varity_R

0.053

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

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