4-143521452-C-T

Variant names:

• chr4-143521452-C-T
• rs112834245
• NM_003601.4:c.276C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_003601.4(SMARCA5):​c.276C>T​(p.Phe92Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.00541 in 1,606,132 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (34 hom.)
• Consequence: SMARCA5 NM_003601.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.22
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 4-143521452-C-T is Benign according to our data. Variant chr4-143521452-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 773457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 716 AD gene.

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.276C>T	p.Phe92Phe	synonymous	Exon 3 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.276C>T	p.Phe92Phe	synonymous	Exon 3 of 24	ENSP00000283131.3	O60264
	SMARCA5	ENST00000940952.1		c.318C>T	p.Phe106Phe	synonymous	Exon 4 of 25	ENSP00000611011.1
	SMARCA5	ENST00000940953.1		c.276C>T	p.Phe92Phe	synonymous	Exon 3 of 24	ENSP00000611012.1

Frequencies

GnomAD3 genomes AF: 0.00474 AC: 715 AN: 150750 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00271

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.0218

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00576

Gnomad OTH AF: 0.00145

GnomAD2 exomes AF: 0.00545 AC: 1351 AN: 247866 AF XY: 0.00555

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.00204

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0216

Gnomad NFE exome AF: 0.00609

Gnomad OTH exome AF: 0.00497

GnomAD4 exome AF: 0.00548 AC: 7980 AN: 1455272 Hom.: 34 Cov.: 31 AF XY: 0.00539 AC XY: 3899 AN XY: 723740

African (AFR) AF: 0.00108 AC: 36 AN: 33228

American (AMR) AF: 0.00208 AC: 92 AN: 44188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25930

East Asian (EAS) AF: 0.00 AC: 0 AN: 39520

South Asian (SAS) AF: 0.00313 AC: 265 AN: 84736

European-Finnish (FIN) AF: 0.0192 AC: 1020 AN: 53226

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5744

European-Non Finnish (NFE) AF: 0.00567 AC: 6289 AN: 1108608

Other (OTH) AF: 0.00451 AC: 271 AN: 60092

GnomAD4 genome AF: 0.00475 AC: 716 AN: 150860 Hom.: 1 Cov.: 32 AF XY: 0.00533 AC XY: 392 AN XY: 73552

African (AFR) AF: 0.00122 AC: 50 AN: 40982

American (AMR) AF: 0.00271 AC: 41 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00167 AC: 8 AN: 4790

European-Finnish (FIN) AF: 0.0218 AC: 223 AN: 10224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00576 AC: 391 AN: 67842

Other (OTH) AF: 0.00143 AC: 3 AN: 2092

Alfa AF: 0.00451 Hom.: 0

Bravo AF: 0.00320

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	12
DANN	Benign	0.74
PhyloP100		4.2
Mutation Taster		=100/0	polymorphism

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: rs112834245; hg19: chr4-144442605;