rs537643024

Variant names:

• chr2-44942165-G-A
• NM_005413.4:c.61G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-44942165-G-A
• chr2-44942165-G-T

Variant summary

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

The NM_005413.4(SIX3):​c.61G>A​(p.Asp21Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SIX3 NM_005413.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85

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]

SIX3-AS1 (HGNC:40532): (SIX3 antisense RNA 1)

ACMG classification

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
SIX3	NM_005413.4	c.61G>A	p.Asp21Asn	missense_variant	Exon 1 of 2	ENST00000260653.5	NP_005404.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIX3	ENST00000260653.5	c.61G>A	p.Asp21Asn	missense_variant	Exon 1 of 2	1	NM_005413.4	ENSP00000260653.3
SIX3-AS1	ENST00000419364.3	n.-249C>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Holoprosencephaly 2 Uncertain:1

May 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 21 of the SIX3 protein (p.Asp21Asn). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with SIX3-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.046
Eigen_PC	Benign	-0.017
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	0.81	L
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.56	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.023	D
Sift4G	Benign	0.13	T
Polyphen		0.65	P
Vest4		0.28
MutPred		0.37		Gain of sheet (P = 0.0149);
MVP		0.93
MPC		1.0
ClinPred		0.65	D
GERP RS		2.7
Varity_R		0.13
gMVP		0.67

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: chr2-45169304; COSMIC: COSV53228551; COSMIC: COSV53228551;