chr7-83405499-T-A

Variant names:

• chr7-83405499-T-A
• rs752718717
• NM_012431.3:c.949A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_012431.3(SEMA3E):​c.949A>T​(p.Thr317Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000146 in 1,612,930 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T317T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: SEMA3E NM_012431.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.78
• Publications: 0 publications found

Genes affected

SEMA3E (HGNC:10727): (semaphorin 3E) Semaphorins are a large family of conserved secreted and membrane associated proteins which possess a semaphorin (Sema) domain and a PSI domain (found in plexins, semaphorins and integrins) in the N-terminal extracellular portion. Based on sequence and structural similarities, semaphorins are put into eight classes: invertebrates contain classes 1 and 2, viruses have class V, and vertebrates contain classes 3-7. Semaphorins serve as axon guidance ligands via multimeric receptor complexes, some (if not all) containing plexin proteins. This gene encodes a class 4 semaphorin. This gene encodes a class 3 semaphorin. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

SEMA3E Gene-Disease associations (from GenCC):

• CHD7-related CHARGE syndrome

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia
• CHARGE syndrome

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• Kallmann syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 7 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012431.3. 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
	SEMA3E	NM_012431.3	MANE Select	c.949A>T	p.Thr317Ser	missense	Exon 9 of 17	NP_036563.1	O15041-1
	SEMA3E	NM_001178129.2		c.769A>T	p.Thr257Ser	missense	Exon 9 of 17	NP_001171600.1	O15041-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA3E	ENST00000643230.2	MANE Select	c.949A>T	p.Thr317Ser	missense	Exon 9 of 17	ENSP00000496491.1	O15041-1
	SEMA3E	ENST00000891111.1		c.949A>T	p.Thr317Ser	missense	Exon 9 of 17	ENSP00000561170.1
	SEMA3E	ENST00000642232.1		c.949A>T	p.Thr317Ser	missense	Exon 9 of 17	ENSP00000494064.1	A0A2R8YCX5

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152020 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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000439 AC: 11 AN: 250812 AF XY: 0.0000369

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: 0.0000882

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000156 AC: 228 AN: 1460910 Hom.: 0 Cov.: 33 AF XY: 0.000157 AC XY: 114 AN XY: 726760

African (AFR) AF: 0.0000299 AC: 1 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.000200 AC: 222 AN: 1111362

Other (OTH) AF: 0.0000829 AC: 5 AN: 60342

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152020 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74232

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000602 Hom.: 0

ExAC AF: 0.0000577 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	CHARGE syndrome (1)
-	1	-	CHARGE syndrome;C0342384:Hypogonadotropic hypogonadism 7 with or without anosmia (1)
-	1	-	not specified (1)
-	1	-	SEMA3E-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.8
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.17
Sift	Benign	0.32	T
Sift4G	Benign	0.31	T
Polyphen		0.91	P
Vest4		0.41
MutPred		0.50		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.60
MPC		0.18
ClinPred		0.32	T
GERP RS		5.9
Varity_R		0.14
gMVP		0.32
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.42		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs752718717; hg19: chr7-83034815;