12-57063278-T-C

Position:

• chr12-57063278-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001130963.2(NEMP1):​c.821A>G​(p.Glu274Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NEMP1 NM_001130963.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.84

Genes affected

NEMP1 (HGNC:29001): (nuclear envelope integral membrane protein 1) Involved in nuclear membrane organization. Predicted to be located in nuclear inner membrane. Predicted to be integral component of membrane. Predicted to be active in nuclear envelope. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEMP1	NM_001130963.2	c.821A>G	p.Glu274Gly	missense_variant	7/9	ENST00000300128.9	NP_001124435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEMP1	ENST00000300128.9	c.821A>G	p.Glu274Gly	missense_variant	7/9	1	NM_001130963.2	ENSP00000300128.4
NEMP1	ENST00000379391.7	c.602A>G	p.Glu201Gly	missense_variant	6/8	1		ENSP00000368701.3
NEMP1	ENST00000554340.1	n.*227A>G		non_coding_transcript_exon_variant	6/8	1		ENSP00000452391.1
NEMP1	ENST00000554340.1	n.*227A>G		3_prime_UTR_variant	6/8	1		ENSP00000452391.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2023

The c.821A>G (p.E274G) alteration is located in exon 7 (coding exon 7) of the NEMP1 gene. This alteration results from a A to G substitution at nucleotide position 821, causing the glutamic acid (E) at amino acid position 274 to be replaced by a glycine (G). 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	Benign	0.19
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Benign	-0.78	T
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Benign	0.22
Sift	Uncertain	0.016	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.97	D;D
Vest4		0.73
MutPred		0.49		.;Loss of stability (P = 0.032);
MVP		0.79
MPC		1.1
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.62
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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: chr12-57457061;