4-143514072-A-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_003601.4(SMARCA5):c.148A>C(p.Ser50Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000074 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMARCA5 NM_003601.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.66

Genes affected

SMARCA5 (HGNC:11101): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 5) The protein encoded by this gene is a member of the SWI/SNF family of proteins. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The protein encoded by this gene is a component of the chromatin remodeling and spacing factor RSF, a facilitator of the transcription of class II genes by RNA polymerase II. The encoded protein is similar in sequence to the Drosophila ISWI chromatin remodeling protein. [provided by RefSeq, Jul 2008]

SMARCA5-AS1 (HGNC:39982): (SMARCA5 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SMARCA5
• BP4: Computational evidence support a benign effect (MetaRNN=0.07930878).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA5	NM_003601.4	c.148A>C	p.Ser50Arg	missense_variant	1/24	ENST00000283131.4
SMARCA5-AS1	NR_104027.1	n.547T>G		non_coding_transcript_exon_variant	2/2
SMARCA5	XM_047416323.1	c.148A>C	p.Ser50Arg	missense_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA5	ENST00000283131.4	c.148A>C	p.Ser50Arg	missense_variant	1/24	1	NM_003601.4	P1
SMARCA5-AS1	ENST00000500800.2	n.345T>G		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 11 AN: 149072 Hom.: 0 Cov.: 33 FAILED QC

Gnomad AFR AF: 0.0000734

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000670

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000706

Gnomad FIN AF: 0.000293

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000227 AC: 301 AN: 1328054 Hom.: 0 Cov.: 31 AF XY: 0.000209 AC XY: 138 AN XY: 659684

Gnomad4 AFR exome AF: 0.000585

Gnomad4 AMR exome AF: 0.000243

Gnomad4 ASJ exome AF: 0.00106

Gnomad4 EAS exome AF: 0.000481

Gnomad4 SAS exome AF: 0.0000246

Gnomad4 FIN exome AF: 0.00122

Gnomad4 NFE exome AF: 0.000175

Gnomad4 OTH exome AF: 0.000377

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000737 AC: 11 AN: 149212 Hom.: 0 Cov.: 33 AF XY: 0.0000823 AC XY: 6 AN XY: 72920

Gnomad4 AFR AF: 0.0000732

Gnomad4 AMR AF: 0.0000668

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000704

Gnomad4 FIN AF: 0.000293

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.148A>C (p.S50R) alteration is located in exon 1 (coding exon 1) of the SMARCA5 gene. This alteration results from a A to C substitution at nucleotide position 148, causing the serine (S) at amino acid position 50 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	0.48
Dann	Benign	0.48
DEOGEN2	Benign	0.25	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0010	N
LIST_S2	Benign	0.36	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.29
Sift	Benign	0.38	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.22		Loss of glycosylation at S50 (P = 0.0058);
MVP		0.33
MPC		0.23
ClinPred		0.064	T
GERP RS		-8.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.049
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs1736766568; hg19: chr4-144435225;