chr7-75421608-T-C

Position:

• chr7-75421608-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The ENST00000615331.5(POM121C):​c.2644A>G​(p.Thr882Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00716 in 1,605,478 control chromosomes in the GnomAD database, including 284 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (62 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (222 hom.)
• Consequence: POM121C ENST00000615331.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.57

Genes affected

POM121C (HGNC:34005): (POM121 transmembrane nucleoporin C) Predicted to enable nuclear localization sequence binding activity. Predicted to be a structural constituent of nuclear pore. Predicted to be involved in RNA export from nucleus and protein import into nucleus. Predicted to be located in nuclear envelope. Predicted to be part of nuclear pore. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), POM121C. . Trascript score misZ 4.3224 (greater than threshold 3.09). GenCC has associacion of gene with schizophrenia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0047879815).
• BP6: Variant 7-75421608-T-C is Benign according to our data. Variant chr7-75421608-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2212045.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0217 (3250/150000) while in subpopulation AFR AF= 0.0338 (1360/40202). AF 95% confidence interval is 0.0323. There are 62 homozygotes in gnomad4. There are 1570 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 62 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POM121C	NM_001099415.3	c.2644A>G	p.Thr882Ala	missense_variant	13/15	ENST00000615331.5	NP_001092885.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POM121C	ENST00000615331.5	c.2644A>G	p.Thr882Ala	missense_variant	13/15	1	NM_001099415.3	ENSP00000481575	A2
POM121C	ENST00000607367.5	c.3370A>G	p.Thr1124Ala	missense_variant	11/13	5		ENSP00000476236	P4

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3253 AN: 149888 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0340

Gnomad AMI AF: 0.0478

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.0220

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.0158

Gnomad FIN AF: 0.0329

Gnomad MID AF: 0.00962

Gnomad NFE AF: 0.0156

Gnomad OTH AF: 0.0116

GnomAD3 exomes AF: 0.00378 AC: 942 AN: 248890 Hom.: 20 AF XY: 0.00336 AC XY: 453 AN XY: 134900

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.00334

Gnomad ASJ exome AF: 0.00230

Gnomad EAS exome AF: 0.00619

Gnomad SAS exome AF: 0.00311

Gnomad FIN exome AF: 0.00154

Gnomad NFE exome AF: 0.00266

Gnomad OTH exome AF: 0.00593

GnomAD4 exome AF: 0.00566 AC: 8242 AN: 1455478 Hom.: 222 Cov.: 31 AF XY: 0.00578 AC XY: 4185 AN XY: 724056

Gnomad4 AFR exome AF: 0.0175

Gnomad4 AMR exome AF: 0.00471

Gnomad4 ASJ exome AF: 0.00961

Gnomad4 EAS exome AF: 0.00976

Gnomad4 SAS exome AF: 0.00872

Gnomad4 FIN exome AF: 0.0190

Gnomad4 NFE exome AF: 0.00407

Gnomad4 OTH exome AF: 0.00872

GnomAD4 genome AF: 0.0217 AC: 3250 AN: 150000 Hom.: 62 Cov.: 32 AF XY: 0.0214 AC XY: 1570 AN XY: 73230

Gnomad4 AFR AF: 0.0338

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.0220

Gnomad4 EAS AF: 0.0160

Gnomad4 SAS AF: 0.0159

Gnomad4 FIN AF: 0.0329

Gnomad4 NFE AF: 0.0156

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00619 Hom.: 3

ExAC AF: 0.000593 AC: 72

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.8
DANN	Benign	0.36
DEOGEN2	Benign	0.019	.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00038	N
LIST_S2	Benign	0.12	T;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
Sift4G	Benign	0.85	T;T
Polyphen		0.0	.;B
Vest4		0.11
MVP		0.030
ClinPred		0.0014	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.018
gMVP		0.26

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: rs236661; hg19: chr7-75050891; COSMIC: COSV57546239; COSMIC: COSV57546239;