chr4-143514002-C-G

Variant names:

• chr4-143514002-C-G
• rs370709174
• NM_003601.4:c.78C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003601.4(SMARCA5):​c.78C>G​(p.Ser26Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S26S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SMARCA5 NM_003601.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17
• Publications: 0 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-AS1 (HGNC:39982): (SMARCA5 antisense RNA 1)

ACMG classification

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=0.11908421).

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.78C>G	p.Ser26Arg	missense	Exon 1 of 24	NP_003592.3
	SMARCA5-AS1	NR_104027.1		n.617G>C		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA5	ENST00000283131.4	TSL:1 MANE Select	c.78C>G	p.Ser26Arg	missense	Exon 1 of 24	ENSP00000283131.3	O60264
	SMARCA5-AS1	ENST00000500800.3	TSL:1	n.415G>C		non_coding_transcript_exon	Exon 2 of 2
	SMARCA5	ENST00000940952.1		c.78C>G	p.Ser26Arg	missense	Exon 1 of 25	ENSP00000611011.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1397502 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 691568

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

African (AFR) AF: 0.00 AC: 0 AN: 31822

American (AMR) AF: 0.00 AC: 0 AN: 37864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25222

East Asian (EAS) AF: 0.00 AC: 0 AN: 36428

South Asian (SAS) AF: 0.00 AC: 0 AN: 81336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1086622

Other (OTH) AF: 0.00 AC: 0 AN: 58320

⚠️ 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.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Benign	0.66
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.27
Sift	Benign	0.53	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.26		Loss of phosphorylation at S26 (P = 0.0044)
MVP		0.50
MPC		0.23
ClinPred		0.093	T
GERP RS		2.3
PromoterAI		0.14	Neutral
Varity_R		0.073
gMVP		0.26
Mutation Taster		=91/9	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: rs370709174; hg19: chr4-144435155;