rs6505776

chr18-12984145-C-Achr18-12984145-C-Gchr18-12984145-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001013437.2(SEH1L):c.1025C>A(p.Thr342Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 1,612,740 control chromosomes in the GnomAD database, including 340,975 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.72 (40939 hom., cov: 34)
  • Exomes 𝑓: 0.64 (300036 hom.)
• Consequence: SEH1L NM_001013437.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37

Genes affected

SEH1L (HGNC:30379): (SEH1 like nucleoporin) The protein encoded by this gene is part of a nuclear pore complex, Nup107-160. This protein contains WD repeats and shares 34% amino acid identity with yeast Seh1 and 30% identity with yeast Sec13. All constituents of the Nup107-160 complex, including this protein, specifically localize to kinetochores in mitosis. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.810506E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEH1L	NM_001013437.2	c.1025C>A	p.Thr342Asn	missense_variant	8/9	ENST00000399892.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEH1L	ENST00000399892.7	c.1025C>A	p.Thr342Asn	missense_variant	8/9	1	NM_001013437.2	P3
SEH1L	ENST00000262124.15	c.1025C>A	p.Thr342Asn	missense_variant	8/9	1		A1
SEH1L	ENST00000590843.1	n.2869C>A		non_coding_transcript_exon_variant	3/4	1
SEH1L	ENST00000592582.5	n.3548C>A		non_coding_transcript_exon_variant	5/6	1

Frequencies

GnomAD3 genomes AF: 0.719 AC: 109436 AN: 152108 Hom.: 40877 Cov.: 34

Gnomad AFR AF: 0.928

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.681

Gnomad ASJ AF: 0.752

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.730

Gnomad FIN AF: 0.612

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.609

Gnomad OTH AF: 0.724

GnomAD3 exomes AF: 0.671 AC: 168518 AN: 251240 Hom.: 57664 AF XY: 0.670 AC XY: 90938 AN XY: 135816

Gnomad AFR exome AF: 0.936

Gnomad AMR exome AF: 0.617

Gnomad ASJ exome AF: 0.766

Gnomad EAS exome AF: 0.786

Gnomad SAS exome AF: 0.719

Gnomad FIN exome AF: 0.612

Gnomad NFE exome AF: 0.622

Gnomad OTH exome AF: 0.649

GnomAD4 exome AF: 0.636 AC: 929302 AN: 1460514 Hom.: 300036 Cov.: 42 AF XY: 0.638 AC XY: 463843 AN XY: 726614

Gnomad4 AFR exome AF: 0.944

Gnomad4 AMR exome AF: 0.622

Gnomad4 ASJ exome AF: 0.757

Gnomad4 EAS exome AF: 0.838

Gnomad4 SAS exome AF: 0.720

Gnomad4 FIN exome AF: 0.604

Gnomad4 NFE exome AF: 0.610

Gnomad4 OTH exome AF: 0.672

GnomAD4 genome AF: 0.720 AC: 109553 AN: 152226 Hom.: 40939 Cov.: 34 AF XY: 0.720 AC XY: 53601 AN XY: 74422

Gnomad4 AFR AF: 0.928

Gnomad4 AMR AF: 0.681

Gnomad4 ASJ AF: 0.752

Gnomad4 EAS AF: 0.805

Gnomad4 SAS AF: 0.730

Gnomad4 FIN AF: 0.612

Gnomad4 NFE AF: 0.609

Gnomad4 OTH AF: 0.728

Alfa AF: 0.646 Hom.: 65034

Bravo AF: 0.735

TwinsUK AF: 0.610 AC: 2261

ALSPAC AF: 0.609 AC: 2347

ESP6500AA AF: 0.921 AC: 4059

ESP6500EA AF: 0.621 AC: 5337

ExAC AF: 0.677 AC: 82181

Asia WGS AF: 0.815 AC: 2832 AN: 3478

EpiCase AF: 0.634

EpiControl AF: 0.644

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	11
Dann	Benign	0.32
DEOGEN2	Benign	0.041	T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.077	T;T
MetaRNN	Benign	5.8e-7	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.6	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.87	N;N
REVEL	Benign	0.10
Sift	Benign	0.80	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.0	B;B
Vest4		0.060
MPC		0.34
ClinPred		0.0021	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.14

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

Publications

LitVar

Other links and lift over

dbSNP: rs6505776; hg19: chr18-12984144; COSMIC: COSV50816465; COSMIC: COSV50816465;