4-143514085-C-T

Position:

• chr4-143514085-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_003601.4(SMARCA5):​c.161C>T​(p.Ala54Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000435 in 1,553,136 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00044 (2 hom.)
• Consequence: SMARCA5 NM_003601.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.592

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 Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SMARCA5
• BP4: Computational evidence support a benign effect (MetaRNN=0.008321255).
• BP6: Variant 4-143514085-C-T is Benign according to our data. Variant chr4-143514085-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3048543.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA5	NM_003601.4	c.161C>T	p.Ala54Val	missense_variant	1/24	ENST00000283131.4
SMARCA5-AS1	NR_104027.1	n.534G>A		non_coding_transcript_exon_variant	2/2
SMARCA5	XM_047416323.1	c.161C>T	p.Ala54Val	missense_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA5	ENST00000283131.4	c.161C>T	p.Ala54Val	missense_variant	1/24	1	NM_003601.4	P1
SMARCA5-AS1	ENST00000500800.2	n.332G>A		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000549 AC: 86 AN: 156676 Hom.: 1 AF XY: 0.000695 AC XY: 61 AN XY: 87810

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000191

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000561

Gnomad OTH exome AF: 0.000931

GnomAD4 exome AF: 0.000438 AC: 614 AN: 1400818 Hom.: 2 Cov.: 31 AF XY: 0.000472 AC XY: 327 AN XY: 693306

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000237

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00111

Gnomad4 FIN exome AF: 0.0000289

Gnomad4 NFE exome AF: 0.000440

Gnomad4 OTH exome AF: 0.000429

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74482

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000416 Hom.: 0

Bravo AF: 0.000348

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000515 AC: 4

ExAC AF: 0.000504 AC: 57

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SMARCA5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0082	N
LIST_S2	Benign	0.64	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.083
Sift	Benign	0.38	T
Sift4G	Benign	0.33	T
Polyphen		0.056	B
Vest4		0.13
MVP		0.38
MPC		0.21
ClinPred		0.015	T
GERP RS		0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.047
gMVP		0.27

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: rs200653868; hg19: chr4-144435238;