4-143514072-A-C

Position:

chr4-143514072-A-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.66

Variant links:

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 links:

SMARCA5-AS1 (HGNC:):

SMARCA5-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA5. . Gene score misZ 5.418 (greater than the threshold 3.09). Trascript score misZ 4.0452 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder.

BP4

Computational evidence support a benign effect (MetaRNN=0.07930878).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA5	NM_003601.4 linkuse as main transcript	c.148A>C	p.Ser50Arg	missense_variant	1/24	ENST00000283131.4	NP_003592.3	O60264
SMARCA5	XM_047416323.1 linkuse as main transcript	c.148A>C	p.Ser50Arg	missense_variant	1/14		XP_047272279.1
SMARCA5-AS1	NR_104027.1 linkuse as main transcript	n.547T>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA5	ENST00000283131.4 linkuse as main transcript	c.148A>C	p.Ser50Arg	missense_variant	1/24	1	NM_003601.4	ENSP00000283131.3		O60264
SMARCA5-AS1	ENST00000500800.2 linkuse as main transcript	n.345T>G		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

149072

Hom.:

Cov.:

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.:

Cov.:

AF XY:

0.000209

AC XY:

138

AN XY:

659684

show subpopulations

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:

AN:

149212

Hom.:

Cov.:

AF XY:

0.0000823

AC XY:

AN XY:

72920

show subpopulations

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

LINK: link

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

BayesDel_noAF

Benign

-0.37

CADD

Benign

0.48

DANN

Benign

0.48

DEOGEN2

Benign

0.25

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0010

LIST_S2

Benign

0.36

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.079

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.0

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.22

REVEL

Benign

0.29

Sift

Benign

0.38

Sift4G

Benign

0.43

Polyphen

0.0

Vest4

0.16

MutPred

0.22

Loss of glycosylation at S50 (P = 0.0058);

MVP

0.33

MPC

0.23

ClinPred

0.064

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over