17-1829683-G-T

Variant names:

• chr17-1829683-G-T
• rs8065937
• NM_052928.3:c.-13+43C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_052928.3(SMYD4):​c.-13+43C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.694 in 153,716 control chromosomes in the GnomAD database, including 38,013 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.69 (37408 hom., cov: 28)
  • Exomes 𝑓: 0.73 (605 hom.)
• Consequence: SMYD4 NM_052928.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.140
• Publications: 11 publications found

Genes affected

SMYD4 (HGNC:21067): (SET and MYND domain containing 4) Predicted to enable metal ion binding activity and methyltransferase activity. Involved in heart development. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

RPA1 (HGNC:10289): (replication protein A1) This gene encodes the largest subunit of the heterotrimeric Replication Protein A (RPA) complex, which binds to single-stranded DNA (ssDNA), forming a nucleoprotein complex that plays an important role in DNA metabolism, being involved in DNA replication, repair, recombination, telomere maintenance, and co-ordinating the cellular response to DNA damage through activation of the ataxia telangiectasia and Rad3-related protein (ATR) kinase. The nucleoprotein complex protects the single-stranded DNA from nucleases, prevents formation of secondary structures that would interfere with repair, and co-ordinates the recruitment and departure of different genome maintenance factors. This subunit contains four oligonucleotide/oligosaccharide-binding (OB) domains, though the majority of ssDNA binding occurs in two of these domains. The heterotrimeric complex has two different modes of ssDNA binding, a low-affinity and high-affinity mode, determined by which ssDNA binding domains are utilized. The different binding modes differ in the length of DNA bound and in the proteins with which it interacts, thereby playing a role in regulating different genomic maintenance pathways. [provided by RefSeq, Sep 2017]

RPA1 Gene-Disease associations (from GenCC):

• pulmonary fibrosis and/or bone marrow failure, telomere-related, 6

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052928.3. 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
	SMYD4	NM_052928.3	MANE Select	c.-13+43C>A		intron	N/A	NP_443160.2	Q8IYR2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMYD4	ENST00000305513.12	TSL:1 MANE Select	c.-13+43C>A		intron	N/A	ENSP00000304360.7	Q8IYR2
	SMYD4	ENST00000954772.1		c.-2+43C>A		intron	N/A	ENSP00000624831.1
	SMYD4	ENST00000954773.1		c.-13+43C>A		intron	N/A	ENSP00000624832.1

Frequencies

GnomAD3 genomes AF: 0.694 AC: 105061 AN: 151476 Hom.: 37383 Cov.: 28

Gnomad AFR AF: 0.680

Gnomad AMI AF: 0.884

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.667

Gnomad EAS AF: 0.412

Gnomad SAS AF: 0.503

Gnomad FIN AF: 0.664

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.777

Gnomad OTH AF: 0.677

GnomAD4 exome AF: 0.726 AC: 1544 AN: 2126 Hom.: 605 Cov.: 0 AF XY: 0.738 AC XY: 788 AN XY: 1068

African (AFR) AF: 0.630 AC: 58 AN: 92

American (AMR) AF: 0.450 AC: 36 AN: 80

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 54 AN: 82

East Asian (EAS) AF: 0.389 AC: 42 AN: 108

South Asian (SAS) AF: 0.700 AC: 21 AN: 30

European-Finnish (FIN) AF: 0.601 AC: 89 AN: 148

Middle Eastern (MID) AF: 0.833 AC: 5 AN: 6

European-Non Finnish (NFE) AF: 0.794 AC: 1136 AN: 1430

Other (OTH) AF: 0.687 AC: 103 AN: 150

GnomAD4 genome AF: 0.694 AC: 105133 AN: 151590 Hom.: 37408 Cov.: 28 AF XY: 0.683 AC XY: 50607 AN XY: 74062

African (AFR) AF: 0.680 AC: 28117 AN: 41338

American (AMR) AF: 0.526 AC: 7985 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 2311 AN: 3464

East Asian (EAS) AF: 0.412 AC: 2090 AN: 5068

South Asian (SAS) AF: 0.504 AC: 2422 AN: 4804

European-Finnish (FIN) AF: 0.664 AC: 6978 AN: 10512

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.777 AC: 52794 AN: 67914

Other (OTH) AF: 0.677 AC: 1425 AN: 2104

Alfa AF: 0.742 Hom.: 145547

Bravo AF: 0.681

Asia WGS AF: 0.436 AC: 1520 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.0
DANN	Benign	0.84
PhyloP100		-0.14
PromoterAI		-0.035	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs8065937; hg19: chr17-1732977; COSMIC: COSV54612871; COSMIC: COSV54612871;