14-60713640-G-C

Variant names:

• chr14-60713640-G-C
• rs1895863132
• NM_017420.5:c.2113C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017420.5(SIX4):​c.2113C>G​(p.Gln705Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SIX4 NM_017420.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.46

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.129498).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX4	NM_017420.5	c.2113C>G	p.Gln705Glu	missense_variant	Exon 3 of 3	ENST00000216513.5	NP_059116.3
SIX4	XM_005267759.3	c.2089C>G	p.Gln697Glu	missense_variant	Exon 4 of 4		XP_005267816.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIX4	ENST00000216513.5	c.2113C>G	p.Gln705Glu	missense_variant	Exon 3 of 3	1	NM_017420.5	ENSP00000216513.4
SIX4	ENST00000554079.1	n.1530C>G		non_coding_transcript_exon_variant	Exon 4 of 4	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461886 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2113C>G (p.Q705E) alteration is located in exon 3 (coding exon 3) of the SIX4 gene. This alteration results from a C to G substitution at nucleotide position 2113, causing the glutamine (Q) at amino acid position 705 to be replaced by a glutamic acid (E). 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	0.070
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.065
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.34	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.21
Sift	Benign	0.068	T
Sift4G	Benign	0.84	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.18		Loss of helix (P = 0.0558);
MVP		0.51
MPC		0.089
ClinPred		0.53	D
GERP RS		4.7
Varity_R		0.21
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1895863132; hg19: chr14-61180358; COSMIC: COSV105086573;