19-10996314-G-C

Variant names:

• chr19-10996314-G-C
• rs1173206989
• NM_001387283.1:c.1695G>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_003072.5(SMARCA4):​c.1695G>C​(p.Thr565Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: SMARCA4 NM_003072.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.76

Genes affected

SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. 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 encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-10996314-G-C is Benign according to our data. Variant chr19-10996314-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2587118.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1695G>C	p.Thr565Thr	synonymous_variant	Exon 10 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1695G>C	p.Thr565Thr	synonymous_variant	Exon 10 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1695G>C	p.Thr565Thr	synonymous_variant	Exon 10 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1695G>C	p.Thr565Thr	synonymous_variant	Exon 10 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1695G>C	p.Thr565Thr	synonymous_variant	Exon 10 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1695G>C	p.Thr565Thr	synonymous_variant	Exon 11 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1695G>C	p.Thr565Thr	synonymous_variant	Exon 10 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1695G>C	p.Thr565Thr	synonymous_variant	Exon 10 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1695G>C	p.Thr565Thr	synonymous_variant	Exon 11 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1107G>C	p.Thr369Thr	synonymous_variant	Exon 7 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.339G>C	p.Thr113Thr	synonymous_variant	Exon 3 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.423G>C	p.Thr141Thr	synonymous_variant	Exon 3 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.183G>C	p.Thr61Thr	synonymous_variant	Exon 2 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.48G>C	p.Thr16Thr	synonymous_variant	Exon 1 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74508

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1

Jun 24, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.15
DANN	Benign	0.67
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1173206989; hg19: chr19-11106990;