rs377320521

Positions:

• chr2-44944585-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005413.4(SIX3):​c.824T>C​(p.Ile275Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000462 in 1,578,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: SIX3 NM_005413.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 5.56

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018870056).
• BP6: Variant 2-44944585-T-C is Benign according to our data. Variant chr2-44944585-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445995.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr2-44944585-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000453 (69/152270) while in subpopulation NFE AF= 0.000897 (61/68008). AF 95% confidence interval is 0.000716. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 69 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIX3	NM_005413.4	c.824T>C	p.Ile275Thr	missense_variant	2/2	ENST00000260653.5	NP_005404.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIX3	ENST00000260653.5	c.824T>C	p.Ile275Thr	missense_variant	2/2	1	NM_005413.4	ENSP00000260653.3

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000344 AC: 67 AN: 194860 Hom.: 0 AF XY: 0.000286 AC XY: 31 AN XY: 108558

Gnomad AFR exome AF: 0.000283

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: 0.000480

Gnomad NFE exome AF: 0.000684

Gnomad OTH exome AF: 0.000194

GnomAD4 exome AF: 0.000463 AC: 660 AN: 1426614 Hom.: 0 Cov.: 31 AF XY: 0.000399 AC XY: 283 AN XY: 708534

Gnomad4 AFR exome AF: 0.000153

Gnomad4 AMR exome AF: 0.0000231

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.000492

Gnomad4 NFE exome AF: 0.000560

Gnomad4 OTH exome AF: 0.000304

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74482

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000446

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000546 AC: 4

ExAC AF: 0.000354 AC: 41

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 02, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The c.824T>C (p.I275T) alteration is located in exon 2 (coding exon 2) of the SIX3 gene. This alteration results from a T to C substitution at nucleotide position 824, causing the isoleucine (I) at amino acid position 275 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Holoprosencephaly 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Benign	0.85
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.55	N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.85	N
REVEL	Uncertain	0.35
Sift	Benign	0.064	T
Sift4G	Benign	0.20	T
Polyphen		0.0060	B
Vest4		0.32
MVP		0.70
MPC		1.3
ClinPred		0.016	T
GERP RS		1.3
Varity_R		0.15
gMVP		0.48

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: rs377320521; hg19: chr2-45171724; COSMIC: COSV53228444; COSMIC: COSV53228444;