14-60509416-C-T

Variant names:

• chr14-60509416-C-T
• rs150715226
• NM_007374.3:c.18C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS1

The NM_007374.3(SIX6):​c.18C>T​(p.Ile6Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,599,560 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 Benign (★). Synonymous variant affecting the same amino acid position (i.e. I6I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: SIX6 NM_007374.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.247
• Publications: 1 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 14-60509416-C-T is Benign according to our data. Variant chr14-60509416-C-T is described in ClinVar as Benign. ClinVar VariationId is 772058.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.247 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000991 (151/152366) while in subpopulation AFR AF = 0.00351 (146/41592). AF 95% confidence interval is 0.00305. There are 0 homozygotes in GnomAd4. There are 81 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.18C>T	p.Ile6Ile	synonymous	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.18C>T	p.Ile6Ile	synonymous	Exon 1 of 2	ENSP00000328596.5	O95475
	C14orf39	ENST00000556799.1	TSL:4	c.-144+5979G>A		intron	N/A	ENSP00000451441.1	G3V3U9

Frequencies

GnomAD3 genomes AF: 0.000992 AC: 151 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000252 AC: 60 AN: 237894 AF XY: 0.000162

Gnomad AFR exome AF: 0.00328

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000897

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000116 AC: 168 AN: 1447194 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 78 AN XY: 720328

African (AFR) AF: 0.00424 AC: 142 AN: 33472

American (AMR) AF: 0.000224 AC: 10 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38936

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111910

Other (OTH) AF: 0.000182 AC: 11 AN: 60306

GnomAD4 genome AF: 0.000991 AC: 151 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.00109 AC XY: 81 AN XY: 74504

African (AFR) AF: 0.00351 AC: 146 AN: 41592

American (AMR) AF: 0.000326 AC: 5 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000869 Hom.: 0

Bravo AF: 0.00120

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	11
DANN	Benign	0.94
PhyloP100		0.25
PromoterAI		-0.024	Neutral

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: rs150715226; hg19: chr14-60976134;