NM_007374.3:c.-147T>C

Variant names:

• chr14-60509252-T-C
• rs551864637
• NM_007374.3:c.-147T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007374.3(SIX6):​c.-147T>C 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 0.00153 in 714,570 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00060 (2 hom.)
• Consequence: SIX6 NM_007374.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.122
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 14-60509252-T-C is Benign according to our data. Variant chr14-60509252-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 882017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00498 (757/152132) while in subpopulation AFR AF = 0.0172 (712/41508). AF 95% confidence interval is 0.0161. There are 6 homozygotes in GnomAd4. There are 335 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.-147T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	NP_031400.2	O95475
	SIX6	NM_007374.3	MANE Select	c.-147T>C		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.-147T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	ENSP00000328596.5	O95475
	SIX6	ENST00000327720.6	TSL:1 MANE Select	c.-147T>C		5_prime_UTR	Exon 1 of 2	ENSP00000328596.5	O95475
	C14orf39	ENST00000556799.1	TSL:4	c.-144+6143A>G		intron	N/A	ENSP00000451441.1	G3V3U9

Frequencies

GnomAD3 genomes AF: 0.00495 AC: 753 AN: 152014 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00431

GnomAD4 exome AF: 0.000597 AC: 336 AN: 562438 Hom.: 2 Cov.: 7 AF XY: 0.000542 AC XY: 161 AN XY: 296976

African (AFR) AF: 0.0147 AC: 228 AN: 15542

American (AMR) AF: 0.00118 AC: 33 AN: 28036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16654

East Asian (EAS) AF: 0.00 AC: 0 AN: 31776

South Asian (SAS) AF: 0.0000542 AC: 3 AN: 55382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31006

Middle Eastern (MID) AF: 0.00265 AC: 9 AN: 3396

European-Non Finnish (NFE) AF: 0.0000456 AC: 16 AN: 350528

Other (OTH) AF: 0.00156 AC: 47 AN: 30118

GnomAD4 genome AF: 0.00498 AC: 757 AN: 152132 Hom.: 6 Cov.: 33 AF XY: 0.00450 AC XY: 335 AN XY: 74366

African (AFR) AF: 0.0172 AC: 712 AN: 41508

American (AMR) AF: 0.00196 AC: 30 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67992

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00437 Hom.: 1

Bravo AF: 0.00542

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Anophthalmia-microphthalmia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.8
DANN	Benign	0.69
PhyloP100		-0.12
PromoterAI		0.033	Neutral
Mutation Taster		=300/0	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: rs551864637; hg19: chr14-60975970; COSMIC: COSV100576554;