5-9050465-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003966.3(SEMA5A):c.2846-8T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 1,611,948 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (28 hom.)
• Consequence: SEMA5A NM_003966.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00008183
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.75

Genes affected

SEMA5A (HGNC:10736): (semaphorin 5A) This gene belongs to the semaphorin gene family that encodes membrane proteins containing a semaphorin domain and several thrombospondin type-1 repeats. Members of this family are involved in axonal guidance during neural development. This gene has been implicated as an autism susceptibility gene.[provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 5-9050465-A-G is Benign according to our data. Variant chr5-9050465-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 777593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA5A	NM_003966.3	c.2846-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000382496.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA5A	ENST00000382496.10	c.2846-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003966.3	P1
SEMA5A	ENST00000652226.1	c.2846-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.00464 AC: 706 AN: 152222 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.00706

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00647

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00424 AC: 1056 AN: 249284 Hom.: 3 AF XY: 0.00442 AC XY: 596 AN XY: 134732

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.00313

Gnomad ASJ exome AF: 0.00818

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00167

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00654

Gnomad OTH exome AF: 0.00563

GnomAD4 exome AF: 0.00523 AC: 7630 AN: 1459608 Hom.: 28 Cov.: 30 AF XY: 0.00526 AC XY: 3819 AN XY: 725998

Gnomad4 AFR exome AF: 0.000808

Gnomad4 AMR exome AF: 0.00333

Gnomad4 ASJ exome AF: 0.00774

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00192

Gnomad4 FIN exome AF: 0.00197

Gnomad4 NFE exome AF: 0.00596

Gnomad4 OTH exome AF: 0.00507

GnomAD4 genome AF: 0.00463 AC: 706 AN: 152340 Hom.: 1 Cov.: 33 AF XY: 0.00474 AC XY: 353 AN XY: 74508

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00705

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.00647

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00504 Hom.: 3

Bravo AF: 0.00470

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	SEMA5A: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	6.3
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000082
dbscSNV1_RF	Benign	0.014
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

Publications

LitVar

Other links and lift over

dbSNP: rs141409163; hg19: chr5-9050577;