19-40441872-C-A

Variant names:

• chr19-40441872-C-A
• rs1352566175
• NM_203344.3:c.209G>T

Variant summary

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

The NM_203344.3(SERTAD3):​c.209G>T​(p.Arg70Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,424,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R70H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SERTAD3 NM_203344.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0960
• Publications: 0 publications found

Genes affected

SERTAD3 (HGNC:17931): (SERTA domain containing 3) The protein encoded by this gene was identified in a yeast two-hybrid assay employing the second subunit of human replication protein A as bait. It is localized to the nucleus and its expression is significantly higher in cancer cell lines compared to normal cell lines. This protein has also been shown to be a strong transcriptional co-activator. Alternative splicing has been observed at this locus and two variants, both encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

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=0.17024761).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203344.3. 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
	SERTAD3	NM_203344.3	MANE Select	c.209G>T	p.Arg70Leu	missense	Exon 2 of 2	NP_976219.1	Q9UJW9
	SERTAD3	NM_013368.4		c.209G>T	p.Arg70Leu	missense	Exon 2 of 2	NP_037500.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERTAD3	ENST00000322354.4	TSL:1 MANE Select	c.209G>T	p.Arg70Leu	missense	Exon 2 of 2	ENSP00000325414.2	Q9UJW9
	SERTAD3	ENST00000392028.9	TSL:1	c.209G>T	p.Arg70Leu	missense	Exon 2 of 2	ENSP00000375882.3
	SERTAD3	ENST00000865349.1		c.209G>T	p.Arg70Leu	missense	Exon 3 of 3	ENSP00000535408.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1424682 Hom.: 0 Cov.: 32 AF XY: 0.00000284 AC XY: 2 AN XY: 705298

⚠️ 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: 32458

American (AMR) AF: 0.00 AC: 0 AN: 39010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23328

East Asian (EAS) AF: 0.00 AC: 0 AN: 39358

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80400

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 51998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5532

European-Non Finnish (NFE) AF: 9.14e-7 AC: 1 AN: 1093900

Other (OTH) AF: 0.00 AC: 0 AN: 58698

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0561929), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	5.5
DANN	Benign	0.71
DEOGEN2	Benign	0.30	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.096
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.26
Sift	Benign	0.18	T
Sift4G	Benign	0.54	T
Polyphen		0.012	B
Vest4		0.23
MutPred		0.61		Loss of methylation at R70 (P = 0.0471)
MVP		0.27
MPC		0.24
ClinPred		0.15	T
GERP RS		-9.7
Varity_R		0.13
gMVP		0.21
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs1352566175; hg19: chr19-40947779;