chr4-143513979-A-C

Position:

• chr4-143513979-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003601.4(SMARCA5):​c.55A>C​(p.Lys19Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA5 NM_003601.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA5. . Gene score misZ 5.418 (greater than the threshold 3.09). Trascript score misZ 4.0452 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1927732).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA5	NM_003601.4	c.55A>C	p.Lys19Gln	missense_variant	1/24	ENST00000283131.4	NP_003592.3
SMARCA5	XM_047416323.1	c.55A>C	p.Lys19Gln	missense_variant	1/14		XP_047272279.1
SMARCA5-AS1	NR_104027.1	n.640T>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA5	ENST00000283131.4	c.55A>C	p.Lys19Gln	missense_variant	1/24	1	NM_003601.4	ENSP00000283131.3
SMARCA5-AS1	ENST00000500800.2	n.438T>G		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2024

The c.55A>C (p.K19Q) alteration is located in exon 1 (coding exon 1) of the SMARCA5 gene. This alteration results from a A to C substitution at nucleotide position 55, causing the lysine (K) at amino acid position 19 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.53
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.16	N
REVEL	Benign	0.19
Sift	Benign	0.15	T
Sift4G	Benign	0.59	T
Polyphen		0.80	P
Vest4		0.26
MutPred		0.23		Loss of ubiquitination at K19 (P = 0.0012);
MVP		0.63
MPC		0.22
ClinPred		0.21	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-144435132;