NM_174978.3:c.1279T>C

Variant names:

• chr14-60456996-A-G
• rs149339653
• NM_174978.3:c.1279T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_174978.3(C14orf39):​c.1279T>C​(p.Phe427Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 1,611,372 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0037 (17 hom.)
• Consequence: C14orf39 NM_174978.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.15
• Publications: 5 publications found

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]

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008772612).
• BP6: Variant 14-60456996-A-G is Benign according to our data. Variant chr14-60456996-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3055519.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 17 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174978.3. 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
	C14orf39	NM_174978.3	MANE Select	c.1279T>C	p.Phe427Leu	missense	Exon 15 of 18	NP_777638.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C14orf39	ENST00000321731.8	TSL:1 MANE Select	c.1279T>C	p.Phe427Leu	missense	Exon 15 of 18	ENSP00000324920.3	Q8N1H7
	C14orf39	ENST00000557138.5	TSL:1	n.*593T>C		non_coding_transcript_exon	Exon 10 of 13	ENSP00000450476.1	G3V257
	C14orf39	ENST00000557138.5	TSL:1	n.*593T>C		3_prime_UTR	Exon 10 of 13	ENSP00000450476.1	G3V257

Frequencies

GnomAD3 genomes AF: 0.00228 AC: 347 AN: 152050 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00366

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00228 AC: 568 AN: 249488 AF XY: 0.00232

Gnomad AFR exome AF: 0.00107

Gnomad AMR exome AF: 0.00126

Gnomad ASJ exome AF: 0.000499

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00227

Gnomad NFE exome AF: 0.00388

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00368 AC: 5371 AN: 1459204 Hom.: 17 Cov.: 30 AF XY: 0.00352 AC XY: 2553 AN XY: 725888

African (AFR) AF: 0.000841 AC: 28 AN: 33296

American (AMR) AF: 0.00112 AC: 50 AN: 44462

Ashkenazi Jewish (ASJ) AF: 0.000384 AC: 10 AN: 26036

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39508

South Asian (SAS) AF: 0.000151 AC: 13 AN: 85968

European-Finnish (FIN) AF: 0.00285 AC: 152 AN: 53372

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5756

European-Non Finnish (NFE) AF: 0.00447 AC: 4959 AN: 1110550

Other (OTH) AF: 0.00259 AC: 156 AN: 60256

GnomAD4 genome AF: 0.00228 AC: 347 AN: 152168 Hom.: 0 Cov.: 31 AF XY: 0.00211 AC XY: 157 AN XY: 74394

African (AFR) AF: 0.000915 AC: 38 AN: 41548

American (AMR) AF: 0.00118 AC: 18 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00311 AC: 33 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00366 AC: 249 AN: 67956

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00327 Hom.: 0

Bravo AF: 0.00216

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00243 AC: 295

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	C14orf39-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	0.13
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.90	T
PhyloP100		2.1
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.11
Sift	Uncertain	0.026	D
Sift4G	Pathogenic	0.0	D
Vest4		0.42
MutPred		0.33		Loss of methylation at K432 (P = 0.073)
MVP		0.072
MPC		0.071
ClinPred		0.042	T
GERP RS		4.2
gMVP		0.062
Mutation Taster		=99/1	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: rs149339653; hg19: chr14-60923714;