14-60455118-T-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_174978.3(C14orf39):c.1386A>C(p.Glu462Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,564,472 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (19 hom.)
• Consequence: C14orf39 NM_174978.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.64

Genes affected

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004501492).
• BP6: Variant 14-60455118-T-G is Benign according to our data. Variant chr14-60455118-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 2644268.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C14orf39	NM_174978.3	c.1386A>C	p.Glu462Asp	missense_variant	16/18	ENST00000321731.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C14orf39	ENST00000321731.8	c.1386A>C	p.Glu462Asp	missense_variant	16/18	1	NM_174978.3	P1
C14orf39	ENST00000557138.5	c.*700A>C		3_prime_UTR_variant, NMD_transcript_variant	11/13	1

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 449 AN: 152010 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00534

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00279 AC: 576 AN: 206180 Hom.: 4 AF XY: 0.00289 AC XY: 326 AN XY: 112796

Gnomad AFR exome AF: 0.000942

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.000126

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000661

Gnomad FIN exome AF: 0.00154

Gnomad NFE exome AF: 0.00460

Gnomad OTH exome AF: 0.00355

GnomAD4 exome AF: 0.00497 AC: 7014 AN: 1412344 Hom.: 19 Cov.: 28 AF XY: 0.00478 AC XY: 3360 AN XY: 703042

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00204

Gnomad4 ASJ exome AF: 0.0000828

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000714

Gnomad4 FIN exome AF: 0.00185

Gnomad4 NFE exome AF: 0.00601

Gnomad4 OTH exome AF: 0.00300

GnomAD4 genome AF: 0.00296 AC: 450 AN: 152128 Hom.: 1 Cov.: 32 AF XY: 0.00277 AC XY: 206 AN XY: 74348

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.00535

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00444 Hom.: 4

Bravo AF: 0.00289

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00489 AC: 42

ExAC AF: 0.00268 AC: 325

Asia WGS AF: 0.000869 AC: 3 AN: 3468

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

C14orf39: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.98	N
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.062
Sift	Benign	0.20	T
Sift4G	Pathogenic	0.0	D
Vest4		0.23
MutPred		0.12		Loss of methylation at K467 (P = 0.1893);
MVP		0.39
MPC		0.088
ClinPred		0.024	T
GERP RS		2.1
gMVP		0.046

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

Publications

LitVar

Other links and lift over

dbSNP: rs139054454; hg19: chr14-60921836;