14-49784976-C-T

Variant names:

• chr14-49784976-C-T
• rs192550021
• NM_004713.6:c.3102G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_004713.6(NEMF):​c.3102G>A​(p.Met1034Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000424 in 1,613,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (0 hom.)
• Consequence: NEMF NM_004713.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.32

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

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13226584).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000236 (36/152222) while in subpopulation AMR AF= 0.000393 (6/15286). AF 95% confidence interval is 0.000243. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEMF	NM_004713.6	c.3102G>A	p.Met1034Ile	missense_variant	Exon 32 of 33	ENST00000298310.10	NP_004704.3
KLHDC2	NM_014315.3	c.*2023C>T		3_prime_UTR_variant	Exon 13 of 13	ENST00000298307.10	NP_055130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEMF	ENST00000298310.10	c.3102G>A	p.Met1034Ile	missense_variant	Exon 32 of 33	5	NM_004713.6	ENSP00000298310.5
KLHDC2	ENST00000298307.10	c.*2023C>T		3_prime_UTR_variant	Exon 13 of 13	1	NM_014315.3	ENSP00000298307.5

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000275 AC: 69 AN: 251030 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135698

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000502

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000443 AC: 648 AN: 1461598 Hom.: 0 Cov.: 30 AF XY: 0.000458 AC XY: 333 AN XY: 727110

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000555

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74420

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.000287

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.000491

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 04, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3102G>A (p.M1034I) alteration is located in exon 32 (coding exon 32) of the NEMF gene. This alteration results from a G to A substitution at nucleotide position 3102, causing the methionine (M) at amino acid position 1034 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.040	T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.23
Sift	Benign	0.27	T;T
Sift4G	Benign	0.23	T;.
Polyphen		0.98	D;.
Vest4		0.61
MutPred		0.32		Loss of catalytic residue at M1034 (P = 0.0477);.;
MVP		0.43
MPC		0.82
ClinPred		0.085	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.43

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: rs192550021; hg19: chr14-50251694; COSMIC: COSV100026900; COSMIC: COSV100026900;