14-49785298-GTCAAAGAA-G

Position:

• chr14-49785298-GTCAAAGAA-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004713.6(NEMF):​c.2943_2950del​(p.Ser982ArgfsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NEMF NM_004713.6 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.92

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-49785298-GTCAAAGAA-G is Pathogenic according to our data. Variant chr14-49785298-GTCAAAGAA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2432191.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEMF	NM_004713.6	c.2943_2950del	p.Ser982ArgfsTer6	frameshift_variant	30/33	ENST00000298310.10	NP_004704.3
KLHDC2	NM_014315.3	c.*2351_*2358del		3_prime_UTR_variant	13/13	ENST00000298307.10	NP_055130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEMF	ENST00000298310.10	c.2943_2950del	p.Ser982ArgfsTer6	frameshift_variant	30/33	5	NM_004713.6	ENSP00000298310	P1
KLHDC2	ENST00000298307.10	c.*2351_*2358del		3_prime_UTR_variant	13/13	1	NM_014315.3	ENSP00000298307	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder with speech delay and axonal peripheral neuropathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

May 26, 2022

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-50252016;