Genetic Variant SMARCA5:p.Ala56Val (chr4-143514091-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003601.4(SMARCA5):c.167C>T(p.Ala56Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,397,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A56S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SMARCA5
NM_003601.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.78

Publications

0 publications found

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:39982): (SMARCA5 antisense RNA 1)

SMARCA5-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09530699).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003601.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA5	NM_003601.4	MANE Select	c.167C>T	p.Ala56Val	missense	Exon 1 of 24	NP_003592.3
	SMARCA5-AS1	NR_104027.1		n.528G>A		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMARCA5	ENST00000283131.4	TSL:1 MANE Select	c.167C>T	p.Ala56Val	missense	Exon 1 of 24	ENSP00000283131.3	O60264
SMARCA5-AS1	ENST00000500800.3	TSL:1	n.326G>A		non_coding_transcript_exon	Exon 2 of 2
SMARCA5	ENST00000940952.1		c.167C>T	p.Ala56Val	missense	Exon 1 of 25	ENSP00000611011.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1397658

Hom.:

Cov.:

AF XY:

0.00000289

AC XY:

AN XY:

691384

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31294

American (AMR)

AF:

0.00

AC:

AN:

37498

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24572

East Asian (EAS)

AF:

0.0000271

AC:

AN:

36914

South Asian (SAS)

AF:

0.0000124

AC:

AN:

80968

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5610

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088042

Other (OTH)

AF:

0.00

AC:

AN:

58136

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.36

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.64

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.095

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.0

PhyloP100

1.8

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.70

REVEL

Benign

0.19

Sift

Benign

0.091

Sift4G

Benign

0.29

Polyphen

0.0010

Vest4

0.071

MutPred

0.20

Gain of loop (P = 0.0051)

MVP

0.30

MPC

0.21

ClinPred

0.051

GERP RS

2.6

PromoterAI

-0.083

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.030

gMVP

0.32

Mutation Taster

=92/8

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over