4-143545951-T-C

Variant names:

• chr4-143545951-T-C
• rs13139128
• NM_003601.4:c.2424T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_003601.4(SMARCA5):​c.2424T>C​(p.Asn808Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,609,866 control chromosomes in the GnomAD database, including 803,448 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 1.0 (75401 hom., cov: 30)
  • Exomes 𝑓: 1.0 (728047 hom.)
• Consequence: SMARCA5 NM_003601.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.589
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP7: Synonymous conserved (PhyloP=0.589 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

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.2424T>C	p.Asn808Asn	synonymous	Exon 19 of 24	NP_003592.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA5	ENST00000283131.4	TSL:1 MANE Select	c.2424T>C	p.Asn808Asn	synonymous	Exon 19 of 24	ENSP00000283131.3	O60264
	SMARCA5	ENST00000940952.1		c.2466T>C	p.Asn822Asn	synonymous	Exon 20 of 25	ENSP00000611011.1
	SMARCA5	ENST00000940953.1		c.2448T>C	p.Asn816Asn	synonymous	Exon 19 of 24	ENSP00000611012.1

Frequencies

GnomAD3 genomes AF: 0.995 AC: 151409 AN: 152136 Hom.: 75348 Cov.: 30

Gnomad AFR AF: 0.983

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.999

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.997

GnomAD2 exomes AF: 0.999 AC: 248587 AN: 248914 AF XY: 0.999

Gnomad AFR exome AF: 0.984

Gnomad AMR exome AF: 0.999

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.999

GnomAD4 exome AF: 0.999 AC: 1456849 AN: 1457612 Hom.: 728047 Cov.: 31 AF XY: 1.00 AC XY: 725032 AN XY: 725388

African (AFR) AF: 0.984 AC: 32660 AN: 33200

American (AMR) AF: 0.999 AC: 43891 AN: 43916

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26069 AN: 26070

East Asian (EAS) AF: 1.00 AC: 39632 AN: 39632

South Asian (SAS) AF: 0.999 AC: 85536 AN: 85632

European-Finnish (FIN) AF: 1.00 AC: 53320 AN: 53320

Middle Eastern (MID) AF: 0.999 AC: 5755 AN: 5758

European-Non Finnish (NFE) AF: 1.00 AC: 1109873 AN: 1109906

Other (OTH) AF: 0.999 AC: 60113 AN: 60178

GnomAD4 genome AF: 0.995 AC: 151521 AN: 152254 Hom.: 75401 Cov.: 30 AF XY: 0.995 AC XY: 74077 AN XY: 74438

African (AFR) AF: 0.983 AC: 40847 AN: 41550

American (AMR) AF: 0.999 AC: 15274 AN: 15290

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5176 AN: 5176

South Asian (SAS) AF: 1.00 AC: 4818 AN: 4820

European-Finnish (FIN) AF: 1.00 AC: 10612 AN: 10612

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68009 AN: 68014

Other (OTH) AF: 0.997 AC: 2107 AN: 2114

Alfa AF: 0.998 Hom.: 32847

Bravo AF: 0.995

Asia WGS AF: 0.998 AC: 3468 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.9
DANN	Benign	0.48
PhyloP100		0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13139128; hg19: chr4-144467104; COSMIC: COSV108045192; COSMIC: COSV108045192;