chr18-12986918-C-T

Variant names:

• chr18-12986918-C-T
• rs138726079
• NM_001013437.2:c.1127C>T

Variant summary

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

The NM_001013437.2(SEH1L):​c.1127C>T​(p.Ala376Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A376G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SEH1L NM_001013437.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.95
• Publications: 0 publications found

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]

CEP192-DT (HGNC:55313): (CEP192 divergent transcript)

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=0.09201589).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001013437.2. 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
	SEH1L	NM_001013437.2	MANE Select	c.1127C>T	p.Ala376Val	missense	Exon 9 of 9	NP_001013455.1	Q96EE3-1
	SEH1L	NM_031216.4		c.*1666C>T		3_prime_UTR	Exon 9 of 9	NP_112493.2	Q96EE3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEH1L	ENST00000399892.7	TSL:1 MANE Select	c.1127C>T	p.Ala376Val	missense	Exon 9 of 9	ENSP00000382779.1	Q96EE3-1
	SEH1L	ENST00000262124.15	TSL:1	c.*1666C>T		3_prime_UTR	Exon 9 of 9	ENSP00000262124.10	Q96EE3-2
	SEH1L	ENST00000590843.1	TSL:1	n.4593C>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151890 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249894 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461136 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726888

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111524

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151890 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74170

African (AFR) AF: 0.00 AC: 0 AN: 41326

American (AMR) AF: 0.00 AC: 0 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Uncertain	0.98
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.9
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.072
Sift	Benign	0.054	T
Sift4G	Benign	0.17	T
Polyphen		0.16	B
Vest4		0.14
MutPred		0.24		Loss of loop (P = 0.1258)
MVP		0.41
MPC		0.34
ClinPred		0.92	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.38
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs138726079; hg19: chr18-12986917;