5-9050437-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003966.3(SEMA5A):c.2866A>G(p.Ser956Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,612,774 control chromosomes in the GnomAD database, including 314 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (36 hom., cov: 33)
  • Exomes 𝑓: 0.016 (278 hom.)
• Consequence: SEMA5A NM_003966.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.42

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036143959).
• BP6: Variant 5-9050437-T-C is Benign according to our data. Variant chr5-9050437-T-C is described in ClinVar as [Benign]. Clinvar id is 2655294.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0138 (2096/152338) while in subpopulation NFE AF= 0.0168 (1140/68028). AF 95% confidence interval is 0.0159. There are 36 homozygotes in gnomad4. There are 1109 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA5A	NM_003966.3	c.2866A>G	p.Ser956Gly	missense_variant	21/23	ENST00000382496.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA5A	ENST00000382496.10	c.2866A>G	p.Ser956Gly	missense_variant	21/23	1	NM_003966.3	P1
SEMA5A	ENST00000652226.1	c.2866A>G	p.Ser956Gly	missense_variant	23/25			P1

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2096 AN: 152220 Hom.: 36 Cov.: 33

Gnomad AFR AF: 0.00301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00739

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0573

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0140 AC: 3501 AN: 250124 Hom.: 64 AF XY: 0.0141 AC XY: 1903 AN XY: 135194

Gnomad AFR exome AF: 0.00259

Gnomad AMR exome AF: 0.00412

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00125

Gnomad FIN exome AF: 0.0508

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.0156 AC: 22773 AN: 1460436 Hom.: 278 Cov.: 30 AF XY: 0.0150 AC XY: 10923 AN XY: 726432

Gnomad4 AFR exome AF: 0.00230

Gnomad4 AMR exome AF: 0.00422

Gnomad4 ASJ exome AF: 0.0191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000991

Gnomad4 FIN exome AF: 0.0502

Gnomad4 NFE exome AF: 0.0166

Gnomad4 OTH exome AF: 0.0132

GnomAD4 genome AF: 0.0138 AC: 2096 AN: 152338 Hom.: 36 Cov.: 33 AF XY: 0.0149 AC XY: 1109 AN XY: 74492

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.00738

Gnomad4 ASJ AF: 0.0205

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0573

Gnomad4 NFE AF: 0.0168

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0148 Hom.: 32

Bravo AF: 0.00986

TwinsUK AF: 0.0156 AC: 58

ALSPAC AF: 0.0163 AC: 63

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0170 AC: 146

ExAC AF: 0.0136 AC: 1654

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0142

EpiControl AF: 0.0156

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

SEMA5A: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.076
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.058
Sift	Benign	0.075	T
Sift4G	Benign	0.088	T
Polyphen		0.0010	B
Vest4		0.19
MPC		0.45
ClinPred		0.010	T
GERP RS		3.7
Varity_R		0.19
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs34563995; hg19: chr5-9050549; COSMIC: COSV99059456; COSMIC: COSV99059456;