rs121917880

chr2-44942853-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PP3_Strong PP5_Moderate

The NM_005413.4(SIX3):c.749T>C(p.Val250Ala) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIX3 NM_005413.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.75

Genes affected

SIX3 (HGNC:10889): (SIX homeobox 3) This gene encodes a member of the sine oculis homeobox transcription factor family. The encoded protein plays a role in eye development. Mutations in this gene have been associated with holoprosencephaly type 2. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity SIX3_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_005413.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 2-44942853-T-C is Pathogenic according to our data. Variant chr2-44942853-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 6095.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIX3	NM_005413.4	c.749T>C	p.Val250Ala	missense_variant	1/2	ENST00000260653.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIX3	ENST00000260653.5	c.749T>C	p.Val250Ala	missense_variant	1/2	1	NM_005413.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1446972 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 720224

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Holoprosencephaly 2 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2004	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Aug 29, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	May 20, 2021	The inherited missense heterozygous variant c.749T>C, p.Val250Ala, identified SIX1 has been reported with the variability of penetrance in multiple individuals and families with holoprosencephaly (PMID:10369266; PMID:15523651; PMID:19346217). This variant is not reported in the gnomAD v3.1 database, indicatinga rare allele, and in silico tools predict a deleterious effect. Functional studies demonstrated that this mutation resulted in the production of a highly unstable proteinin Neuro-2a cells (PMID:15523651). Based on the available evidence, the variant c.749T>C, p.Val250Ala in the SIX3 gene is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	35
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.96		Gain of disorder (P = 0.0152);
MVP		0.99
MPC		2.4
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.96
gMVP		0.97

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

Other links and lift over

dbSNP: rs121917880; hg19: chr2-45169992;