rs1976165

chr17-28959833-T-C

Variant summary

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

The NM_178860.5(SEZ6):c.1636A>G(p.Thr546Ala) variant causes a missense change. The variant allele was found at a frequency of 0.27 in 1,613,136 control chromosomes in the GnomAD database, including 61,549 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.32 (8366 hom., cov: 32)
  • Exomes 𝑓: 0.27 (53183 hom.)
• Consequence: SEZ6 NM_178860.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.86

Genes affected

SEZ6 (HGNC:15955): (seizure related 6 homolog) The protein encoded by this gene is thought to contain five cysteine-rich motifs that are similar to sushi domains, as well as two domains similar to the amino terminal half of the CUB (for complement C1r/C1s, Uegf, Bmp1) domain. Mutations in this gene have been associated with febrile seizures. [provided by RefSeq, Jul 2016]

LOC105371716 (HGNC:):

PIPOX (HGNC:17804): (pipecolic acid and sarcosine oxidase) Enables L-pipecolate oxidase activity and sarcosine oxidase activity. Involved in L-lysine catabolic process to acetyl-CoA via L-pipecolate. Located in peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002216816).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEZ6	NM_178860.5	c.1636A>G	p.Thr546Ala	missense_variant	8/17	ENST00000317338.17
LOC105371716	XR_001752822.2	n.1807+6425T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEZ6	ENST00000317338.17	c.1636A>G	p.Thr546Ala	missense_variant	8/17	1	NM_178860.5	A2

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48194 AN: 151970 Hom.: 8360 Cov.: 32

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.327

GnomAD3 exomes AF: 0.283 AC: 70036 AN: 247794 Hom.: 10464 AF XY: 0.284 AC XY: 38144 AN XY: 134464

Gnomad AFR exome AF: 0.465

Gnomad AMR exome AF: 0.259

Gnomad ASJ exome AF: 0.271

Gnomad EAS exome AF: 0.240

Gnomad SAS exome AF: 0.374

Gnomad FIN exome AF: 0.267

Gnomad NFE exome AF: 0.251

Gnomad OTH exome AF: 0.279

GnomAD4 exome AF: 0.265 AC: 387339 AN: 1461046 Hom.: 53183 Cov.: 36 AF XY: 0.267 AC XY: 194316 AN XY: 726752

Gnomad4 AFR exome AF: 0.469

Gnomad4 AMR exome AF: 0.268

Gnomad4 ASJ exome AF: 0.270

Gnomad4 EAS exome AF: 0.248

Gnomad4 SAS exome AF: 0.363

Gnomad4 FIN exome AF: 0.264

Gnomad4 NFE exome AF: 0.250

Gnomad4 OTH exome AF: 0.288

GnomAD4 genome AF: 0.317 AC: 48231 AN: 152090 Hom.: 8366 Cov.: 32 AF XY: 0.317 AC XY: 23575 AN XY: 74362

Gnomad4 AFR AF: 0.460

Gnomad4 AMR AF: 0.300

Gnomad4 ASJ AF: 0.277

Gnomad4 EAS AF: 0.239

Gnomad4 SAS AF: 0.364

Gnomad4 FIN AF: 0.266

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.324

Alfa AF: 0.266 Hom.: 13592

Bravo AF: 0.326

TwinsUK AF: 0.248 AC: 920

ALSPAC AF: 0.253 AC: 975

ESP6500AA AF: 0.429 AC: 1790

ESP6500EA AF: 0.255 AC: 2162

ExAC AF: 0.287 AC: 34741

Asia WGS AF: 0.339 AC: 1182 AN: 3478

EpiCase AF: 0.254

EpiControl AF: 0.262

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	21
Dann	Benign	0.94
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.44	T;T;T;T;T
MetaRNN	Benign	0.0022	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.73	N;.;N;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.26	N;.;.;.;N
REVEL	Benign	0.079
Sift	Benign	0.31	T;.;.;.;T
Sift4G	Benign	0.19	T;T;T;T;T
Polyphen		0.0	B;.;B;.;.
Vest4		0.033
MPC		0.26
ClinPred		0.0076	T
GERP RS		5.1
Varity_R		0.067
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1976165; hg19: chr17-27286851; COSMIC: COSV100252716; COSMIC: COSV100252716;