14-49785313-A-T

Variant names:

• chr14-49785313-A-T
• rs1890115830
• NM_004713.6:c.2936T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004713.6(NEMF):​c.2936T>A​(p.Leu979Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L979P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEMF NM_004713.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.52
• Publications: 0 publications found

Genes affected

NEMF (HGNC:10663): (nuclear export mediator factor) This gene encodes a component of the ribosome quality control complex. The encoded protein facilitates the recognition and ubiquitination of stalled 60S subunits by the ubiquitin ligase listerin. A similar protein in fly functions as a tumor suppressor. [provided by RefSeq, Jul 2016]

KLHDC2 (HGNC:20231): (kelch domain containing 2) Enables ubiquitin ligase-substrate adaptor activity. Involved in ubiquitin-dependent protein catabolic process via the C-end degron rule pathway. Located in nuclear body and nuclear membrane. Is active in Cul2-RING ubiquitin ligase complex and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004713.6. 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
	NEMF	NM_004713.6	MANE Select	c.2936T>A	p.Leu979Gln	missense	Exon 30 of 33	NP_004704.3
	KLHDC2	NM_014315.3	MANE Select	c.*2360A>T		3_prime_UTR	Exon 13 of 13	NP_055130.1	Q9Y2U9-1
	NEMF	NM_001301732.3		c.2873T>A	p.Leu958Gln	missense	Exon 29 of 32	NP_001288661.2	O60524-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEMF	ENST00000298310.10	TSL:5 MANE Select	c.2936T>A	p.Leu979Gln	missense	Exon 30 of 33	ENSP00000298310.5	O60524-1
	KLHDC2	ENST00000298307.10	TSL:1 MANE Select	c.*2360A>T		3_prime_UTR	Exon 13 of 13	ENSP00000298307.5	Q9Y2U9-1
	NEMF	ENST00000556074.5	TSL:1	n.1760T>A		non_coding_transcript_exon	Exon 9 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.35		Loss of stability (P = 0.0137)
MVP		0.24
MPC		0.83
ClinPred		0.94	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.44
Mutation Taster		=38/62	disease causing

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: rs1890115830; hg19: chr14-50252031;