rs10234961

Variant names:

• chr7-84002074-C-G
• rs10234961
• NM_006080.3:c.1361-28G>C

Variant summary

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

The NM_006080.3(SEMA3A):​c.1361-28G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,302,130 control chromosomes in the GnomAD database, including 472 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (221 hom., cov: 33)
  • Exomes 𝑓: 0.013 (251 hom.)
• Consequence: SEMA3A NM_006080.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.325
• Publications: 2 publications found

Genes affected

SEMA3A (HGNC:10723): (semaphorin 3A) This gene is a member of the semaphorin family and encodes a protein with an Ig-like C2-type (immunoglobulin-like) domain, a PSI domain and a Sema domain. This secreted protein can function as either a chemorepulsive agent, inhibiting axonal outgrowth, or as a chemoattractive agent, stimulating the growth of apical dendrites. In both cases, the protein is vital for normal neuronal pattern development. Increased expression of this protein is associated with schizophrenia and is seen in a variety of human tumor cell lines. Also, aberrant release of this protein is associated with the progression of Alzheimer's disease. [provided by RefSeq, Jul 2008]

SEMA3A Gene-Disease associations (from GenCC):

• skeletal dysplasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• hypogonadotropic hypogonadism 16 with or without anosmia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-84002074-C-G is Benign according to our data. Variant chr7-84002074-C-G is described in ClinVar as Benign. ClinVar VariationId is 1183281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA3A	NM_006080.3	c.1361-28G>C		intron_variant	Intron 11 of 16	ENST00000265362.9	NP_006071.1
SEMA3A	XM_005250110.4	c.1361-28G>C		intron_variant	Intron 14 of 19		XP_005250167.1
SEMA3A	XM_047419751.1	c.1361-28G>C		intron_variant	Intron 15 of 20		XP_047275707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA3A	ENST00000265362.9	c.1361-28G>C		intron_variant	Intron 11 of 16	1	NM_006080.3	ENSP00000265362.3
SEMA3A	ENST00000436949.5	c.1361-28G>C		intron_variant	Intron 12 of 17	5		ENSP00000415260.1

Frequencies

GnomAD3 genomes AF: 0.0348 AC: 5295 AN: 152060 Hom.: 220 Cov.: 33

Gnomad AFR AF: 0.0990

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.0183

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.00943

Gnomad OTH AF: 0.0311

GnomAD2 exomes AF: 0.0171 AC: 4095 AN: 239940 AF XY: 0.0167

Gnomad AFR exome AF: 0.0991

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.0145

Gnomad EAS exome AF: 0.0171

Gnomad FIN exome AF: 0.00123

Gnomad NFE exome AF: 0.00958

Gnomad OTH exome AF: 0.0151

GnomAD4 exome AF: 0.0128 AC: 14696 AN: 1149950 Hom.: 251 Cov.: 15 AF XY: 0.0129 AC XY: 7561 AN XY: 587198

African (AFR) AF: 0.102 AC: 2750 AN: 27078

American (AMR) AF: 0.0113 AC: 476 AN: 42226

Ashkenazi Jewish (ASJ) AF: 0.0131 AC: 311 AN: 23682

East Asian (EAS) AF: 0.0138 AC: 520 AN: 37766

South Asian (SAS) AF: 0.0210 AC: 1651 AN: 78678

European-Finnish (FIN) AF: 0.00153 AC: 81 AN: 52840

Middle Eastern (MID) AF: 0.0573 AC: 296 AN: 5168

European-Non Finnish (NFE) AF: 0.00919 AC: 7650 AN: 832630

Other (OTH) AF: 0.0193 AC: 961 AN: 49882

GnomAD4 genome AF: 0.0349 AC: 5312 AN: 152180 Hom.: 221 Cov.: 33 AF XY: 0.0337 AC XY: 2507 AN XY: 74398

African (AFR) AF: 0.0991 AC: 4114 AN: 41512

American (AMR) AF: 0.0143 AC: 219 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3468

East Asian (EAS) AF: 0.0188 AC: 97 AN: 5168

South Asian (SAS) AF: 0.0209 AC: 101 AN: 4830

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10602

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.00943 AC: 641 AN: 68000

Other (OTH) AF: 0.0307 AC: 65 AN: 2114

Alfa AF: 0.0229 Hom.: 14

Bravo AF: 0.0381

Asia WGS AF: 0.0210 AC: 74 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.0
DANN	Benign	0.62
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10234961; hg19: chr7-83631390;