chr14-60509408-C-A

Variant names:

• chr14-60509408-C-A
• rs372811052
• NM_007374.3:c.10C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BS1_Supporting

The NM_007374.3(SIX6):​c.10C>A​(p.Leu4Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,447,096 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L4L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: SIX6 NM_007374.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77
• Publications: 0 publications found

Genes affected

SIX6 (HGNC:10892): (SIX homeobox 6) The protein encoded by this gene is a homeobox protein that is similar to the Drosophila 'sine oculis' gene product. This gene is found in a cluster of related genes on chromosome 14 and is thought to be involved in eye development. Defects in this gene are a cause of isolated microphthalmia with cataract type 2 (MCOPCT2). [provided by RefSeq, Jul 2008]

C14orf39 (HGNC:19849): (chromosome 14 open reading frame 39) Predicted to be involved in gamete generation and meiosis I. Predicted to be located in chromosome. Predicted to be active in central element. Implicated in primary ovarian insufficiency 18 and spermatogenic failure 52. [provided by Alliance of Genome Resources, Apr 2022]

C14orf39 Gene-Disease associations (from GenCC):

• premature ovarian failure 18

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• spermatogenic failure 52

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31420887).
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000018 (26/1447096) while in subpopulation AFR AF = 0.0000299 (1/33472). AF 95% confidence interval is 0.0000154. There are 0 homozygotes in GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007374.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX6	NM_007374.3	MANE Select	c.10C>A	p.Leu4Met	missense	Exon 1 of 2	NP_031400.2	O95475

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX6	ENST00000327720.6	TSL:1 MANE Select	c.10C>A	p.Leu4Met	missense	Exon 1 of 2	ENSP00000328596.5	O95475
	C14orf39	ENST00000556799.1	TSL:4	c.-144+5987G>T		intron	N/A	ENSP00000451441.1	G3V3U9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000421 AC: 1 AN: 237590 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000180 AC: 26 AN: 1447096 Hom.: 0 Cov.: 31 AF XY: 0.0000139 AC XY: 10 AN XY: 720288

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111866

Other (OTH) AF: 0.00 AC: 0 AN: 60306

GnomAD4 genome Cov.: 33

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000829 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.64
Sift	Uncertain	0.012	D
Sift4G	Benign	0.063	T
Polyphen		0.95	P
Vest4		0.42
MVP		0.83
MPC		1.1
ClinPred		0.66	D
GERP RS		3.7
PromoterAI		-0.012	Neutral
Varity_R		0.33
gMVP		0.43
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs372811052; hg19: chr14-60976126;