chr7-83408415-C-G

Variant names:

• chr7-83408415-C-G
• rs61729612
• NM_012431.3:c.623G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012431.3(SEMA3E):​c.623G>C​(p.Arg208Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,613,448 control chromosomes in the GnomAD database, including 11,976 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R208R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (985 hom., cov: 33)
  • Exomes 𝑓: 0.12 (10991 hom.)
• Consequence: SEMA3E NM_012431.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.678
• Publications: 22 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017450154).
• BP6: Variant 7-83408415-C-G is Benign according to our data. Variant chr7-83408415-C-G is described in ClinVar as Benign. ClinVar VariationId is 260256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

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.623G>C	p.Arg208Pro	missense	Exon 6 of 17	NP_036563.1	O15041-1
	SEMA3E	NM_001178129.2		c.443G>C	p.Arg148Pro	missense	Exon 6 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.623G>C	p.Arg208Pro	missense	Exon 6 of 17	ENSP00000496491.1	O15041-1
	SEMA3E	ENST00000891111.1		c.623G>C	p.Arg208Pro	missense	Exon 6 of 17	ENSP00000561170.1
	SEMA3E	ENST00000642232.1		c.623G>C	p.Arg208Pro	missense	Exon 6 of 17	ENSP00000494064.1	A0A2R8YCX5

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16773 AN: 152102 Hom.: 984 Cov.: 33

Gnomad AFR AF: 0.0770

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.0651

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.119

GnomAD2 exomes AF: 0.117 AC: 29289 AN: 250778 AF XY: 0.116

Gnomad AFR exome AF: 0.0739

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.237

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.119 AC: 173892 AN: 1461232 Hom.: 10991 Cov.: 32 AF XY: 0.118 AC XY: 85767 AN XY: 726894

African (AFR) AF: 0.0753 AC: 2521 AN: 33466

American (AMR) AF: 0.123 AC: 5505 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 6194 AN: 26130

East Asian (EAS) AF: 0.166 AC: 6606 AN: 39678

South Asian (SAS) AF: 0.0662 AC: 5711 AN: 86250

European-Finnish (FIN) AF: 0.110 AC: 5888 AN: 53386

Middle Eastern (MID) AF: 0.152 AC: 876 AN: 5766

European-Non Finnish (NFE) AF: 0.120 AC: 133124 AN: 1111576

Other (OTH) AF: 0.124 AC: 7467 AN: 60358

GnomAD4 genome AF: 0.110 AC: 16777 AN: 152216 Hom.: 985 Cov.: 33 AF XY: 0.111 AC XY: 8257 AN XY: 74400

African (AFR) AF: 0.0770 AC: 3197 AN: 41538

American (AMR) AF: 0.119 AC: 1812 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 848 AN: 3472

East Asian (EAS) AF: 0.146 AC: 754 AN: 5154

South Asian (SAS) AF: 0.0654 AC: 316 AN: 4832

European-Finnish (FIN) AF: 0.105 AC: 1117 AN: 10602

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.123 AC: 8334 AN: 68024

Other (OTH) AF: 0.118 AC: 250 AN: 2114

Alfa AF: 0.129 Hom.: 1066

Bravo AF: 0.109

TwinsUK AF: 0.119 AC: 441

ALSPAC AF: 0.125 AC: 481

ESP6500AA AF: 0.0785 AC: 346

ESP6500EA AF: 0.129 AC: 1106

ExAC AF: 0.113 AC: 13722

Asia WGS AF: 0.107 AC: 371 AN: 3478

EpiCase AF: 0.130

EpiControl AF: 0.134

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	CHARGE syndrome (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.68
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.049
Sift	Benign	0.54	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.22
MPC		0.64
ClinPred		0.014	T
GERP RS		1.9
Varity_R		0.24
gMVP		0.64
Mutation Taster		=98/2	polymorphism (auto)

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: rs61729612; hg19: chr7-83037731; COSMIC: COSV57100584;