rs33912345

Variant names:

• chr14-60509819-C-A
• rs33912345
• NM_007374.3:c.421C>A

Your query was ambiguous. Multiple possible variants found:

• chr14-60509819-C-A
• chr14-60509819-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007374.3(SIX6):​c.421C>A​(p.His141Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 1,612,972 control chromosomes in the GnomAD database, including 270,703 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (19710 hom., cov: 32)
  • Exomes 𝑓: 0.57 (250993 hom.)
• Consequence: SIX6 NM_007374.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.21
• Publications: 101 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 (MetaRNN=5.372838E-6).
• BP6: Variant 14-60509819-C-A is Benign according to our data. Variant chr14-60509819-C-A is described in ClinVar as Benign. ClinVar VariationId is 260163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

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.421C>A	p.His141Asn	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.421C>A	p.His141Asn	missense	Exon 1 of 2	ENSP00000328596.5	O95475
	C14orf39	ENST00000556799.1	TSL:4	c.-144+5576G>T		intron	N/A	ENSP00000451441.1	G3V3U9

Frequencies

GnomAD3 genomes AF: 0.454 AC: 69053 AN: 151962 Hom.: 19703 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.558

Gnomad AMR AF: 0.593

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.728

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.604

Gnomad OTH AF: 0.431

GnomAD2 exomes AF: 0.531 AC: 132666 AN: 249984 AF XY: 0.530

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.682

Gnomad ASJ exome AF: 0.506

Gnomad EAS exome AF: 0.218

Gnomad FIN exome AF: 0.724

Gnomad NFE exome AF: 0.589

Gnomad OTH exome AF: 0.540

GnomAD4 exome AF: 0.575 AC: 839544 AN: 1460892 Hom.: 250993 Cov.: 62 AF XY: 0.571 AC XY: 414937 AN XY: 726586

African (AFR) AF: 0.0962 AC: 3221 AN: 33470

American (AMR) AF: 0.671 AC: 29942 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 13031 AN: 26130

East Asian (EAS) AF: 0.226 AC: 8951 AN: 39666

South Asian (SAS) AF: 0.432 AC: 37227 AN: 86218

European-Finnish (FIN) AF: 0.717 AC: 38279 AN: 53366

Middle Eastern (MID) AF: 0.398 AC: 2298 AN: 5768

European-Non Finnish (NFE) AF: 0.608 AC: 675390 AN: 1111316

Other (OTH) AF: 0.517 AC: 31205 AN: 60350

GnomAD4 genome AF: 0.454 AC: 69077 AN: 152080 Hom.: 19710 Cov.: 32 AF XY: 0.460 AC XY: 34213 AN XY: 74336

African (AFR) AF: 0.115 AC: 4793 AN: 41534

American (AMR) AF: 0.594 AC: 9065 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1764 AN: 3462

East Asian (EAS) AF: 0.229 AC: 1180 AN: 5160

South Asian (SAS) AF: 0.419 AC: 2019 AN: 4816

European-Finnish (FIN) AF: 0.728 AC: 7698 AN: 10568

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.604 AC: 41040 AN: 67962

Other (OTH) AF: 0.429 AC: 903 AN: 2106

Alfa AF: 0.525 Hom.: 58311

Bravo AF: 0.430

TwinsUK AF: 0.583 AC: 2160

ALSPAC AF: 0.609 AC: 2347

ESP6500AA AF: 0.117 AC: 514

ESP6500EA AF: 0.599 AC: 5151

ExAC AF: 0.514 AC: 62376

Asia WGS AF: 0.323 AC: 1126 AN: 3478

EpiCase AF: 0.576

EpiControl AF: 0.563

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome (2)
-	-	2	not specified (2)
-	-	1	Anophthalmia-microphthalmia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.27
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0000054	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.5	N
PhyloP100		3.2
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	1.0	N
REVEL	Uncertain	0.45
Sift	Benign	0.55	T
Sift4G	Benign	0.93	T
Polyphen		0.0	B
Vest4		0.14
MPC		0.96
ClinPred		0.023	T
GERP RS		5.4
Varity_R		0.25
gMVP		0.54
Mutation Taster		=88/12	polymorphism (auto)

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: rs33912345; hg19: chr14-60976537; COSMIC: COSV59802228;