12-57069252-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001130963.2(NEMP1):c.527G>A(p.Cys176Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,394,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: NEMP1 NM_001130963.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.88

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16473037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEMP1	NM_001130963.2	c.527G>A	p.Cys176Tyr	missense_variant	4/9	ENST00000300128.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEMP1	ENST00000300128.9	c.527G>A	p.Cys176Tyr	missense_variant	4/9	1	NM_001130963.2	P1
NEMP1	ENST00000379391.7	c.326+1568G>A		intron_variant		1
NEMP1	ENST00000554340.1	c.*48G>A		3_prime_UTR_variant, NMD_transcript_variant	4/8	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000158 AC: 22 AN: 1394726 Hom.: 0 Cov.: 29 AF XY: 0.0000160 AC XY: 11 AN XY: 687802

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000195

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

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

Oct 05, 2023

The c.527G>A (p.C176Y) alteration is located in exon 4 (coding exon 4) of the NEMP1 gene. This alteration results from a G to A substitution at nucleotide position 527, causing the cysteine (C) at amino acid position 176 to be replaced by a tyrosine (Y). 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	0.24
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	22
Dann	Benign	0.59
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.021
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.12	B
Vest4		0.40
MutPred		0.72		Gain of sheet (P = 0.1208);
MVP		0.50
MPC		1.1
ClinPred		0.64	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.072
gMVP		0.81

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: rs778839804; hg19: chr12-57463035;