7-72929969-C-T

Variant names:

• chr7-72929969-C-T
• rs547650712
• NM_001387691.1:c.1133C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001387691.1(POM121):​c.1133C>T​(p.Ser378Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,612,286 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S378C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POM121 NM_001387691.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.98
• Publications: 0 publications found

Genes affected

POM121 (HGNC:19702): (POM121 transmembrane nucleoporin) This gene encodes a transmembrane protein that localizes to the inner nuclear membrane and forms a core component of the nuclear pore complex, which mediates transport to and from the nucleus. The encoded protein may anchor this complex to the nuclear envelope. There are multiple related genes and pseudogenes for this gene on chromosomes 5, 7, 15, and 22. Alternatively spliced transcript variants encoding different isoforms have been observed. [provided by RefSeq, Jul 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20443884).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387691.1. 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
	POM121	NM_001387691.1	MANE Select	c.1133C>T	p.Ser378Phe	missense	Exon 5 of 13	NP_001374620.1	Q96HA1-1
	POM121	NM_001387692.1		c.1133C>T	p.Ser378Phe	missense	Exon 5 of 12	NP_001374621.1
	POM121	NM_001387693.1		c.1133C>T	p.Ser378Phe	missense	Exon 5 of 10	NP_001374622.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POM121	ENST00000434423.5	TSL:5 MANE Select	c.1133C>T	p.Ser378Phe	missense	Exon 5 of 13	ENSP00000405562.2	Q96HA1-1
	POM121	ENST00000395270.5	TSL:1	c.338C>T	p.Ser113Phe	missense	Exon 8 of 16	ENSP00000378687.1	Q96HA1-3
	POM121	ENST00000897647.1		c.1133C>T	p.Ser378Phe	missense	Exon 5 of 12	ENSP00000567706.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459958 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726136

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110714

Other (OTH) AF: 0.00 AC: 0 AN: 60302

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74502

African (AFR) AF: 0.0000722 AC: 3 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.10
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.46
MutPred		0.17		Loss of phosphorylation at S378 (P = 0.0266)
MVP		0.12
ClinPred		0.97	D
GERP RS		4.1
Varity_R		0.40
gMVP		0.32
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs547650712; hg19: chr7-72400507;