chr14-60509250-C-T

Variant names:

• chr14-60509250-C-T
• rs538661695
• NM_007374.3:c.-149C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_007374.3(SIX6):​c.-149C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 702,634 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (9 hom.)
• Consequence: SIX6 NM_007374.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.236
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 14-60509250-C-T is Benign according to our data. Variant chr14-60509250-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 313427.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00111 (169/152258) while in subpopulation EAS AF = 0.0189 (97/5142). AF 95% confidence interval is 0.0158. There are 2 homozygotes in GnomAd4. There are 107 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.-149C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	NP_031400.2	O95475
	SIX6	NM_007374.3	MANE Select	c.-149C>T		5_prime_UTR	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.-149C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	ENSP00000328596.5	O95475
	SIX6	ENST00000327720.6	TSL:1 MANE Select	c.-149C>T		5_prime_UTR	Exon 1 of 2	ENSP00000328596.5	O95475
	C14orf39	ENST00000556799.1	TSL:4	c.-144+6145G>A		intron	N/A	ENSP00000451441.1	G3V3U9

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152140 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0188

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.00146 AC: 806 AN: 550376 Hom.: 9 Cov.: 7 AF XY: 0.00135 AC XY: 392 AN XY: 291018

African (AFR) AF: 0.0000654 AC: 1 AN: 15294

American (AMR) AF: 0.00598 AC: 167 AN: 27920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16502

East Asian (EAS) AF: 0.0178 AC: 565 AN: 31730

South Asian (SAS) AF: 0.000401 AC: 22 AN: 54886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3344

European-Non Finnish (NFE) AF: 0.0000529 AC: 18 AN: 340014

Other (OTH) AF: 0.00111 AC: 33 AN: 29786

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152258 Hom.: 2 Cov.: 33 AF XY: 0.00144 AC XY: 107 AN XY: 74440

African (AFR) AF: 0.000120 AC: 5 AN: 41556

American (AMR) AF: 0.00385 AC: 59 AN: 15310

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

East Asian (EAS) AF: 0.0189 AC: 97 AN: 5142

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00187

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Anophthalmia-microphthalmia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.6
DANN	Benign	0.91
PhyloP100		-0.24
PromoterAI		0.022	Neutral
Mutation Taster		=297/3	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: rs538661695; hg19: chr14-60975968;