rs3745802

Variant names:

• chr19-45767919-G-T
• rs3745802
• NM_175875.5:c.803+123C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_175875.5(SIX5):​c.803+123C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 1,052,008 control chromosomes in the GnomAD database, including 121,433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17269 hom., cov: 34)
  • Exomes 𝑓: 0.48 (104164 hom.)
• Consequence: SIX5 NM_175875.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.277
• Publications: 9 publications found

Genes affected

SIX5 (HGNC:10891): (SIX homeobox 5) The protein encoded by this gene is a homeodomain-containing transcription factor that appears to function in the regulation of organogenesis. This gene is located downstream of the dystrophia myotonica-protein kinase gene. Mutations in this gene are a cause of branchiootorenal syndrome type 2. [provided by RefSeq, Jul 2009]

DM1-AS (HGNC:53125): (DM1 locus antisense RNA)

ENSG00000259605 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-45767919-G-T is Benign according to our data. Variant chr19-45767919-G-T is described in ClinVar as Benign. ClinVar VariationId is 1174287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175875.5. 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
	SIX5	NM_175875.5	MANE Select	c.803+123C>A		intron	N/A	NP_787071.3
	DM1-AS	NR_147193.1		n.124G>T		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX5	ENST00000317578.7	TSL:1 MANE Select	c.803+123C>A		intron	N/A	ENSP00000316842.4	Q8N196
	SIX5	ENST00000560160.1	TSL:2	c.584+123C>A		intron	N/A	ENSP00000453239.2	H0YLK1
	SIX5	ENST00000560168.1	TSL:4	c.201+123C>A		intron	N/A	ENSP00000453189.2	H0YLF6

Frequencies

GnomAD3 genomes AF: 0.471 AC: 71630 AN: 151956 Hom.: 17255 Cov.: 34

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.591

Gnomad ASJ AF: 0.391

Gnomad EAS AF: 0.642

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.460

Gnomad OTH AF: 0.481

GnomAD4 exome AF: 0.475 AC: 427807 AN: 899934 Hom.: 104164 Cov.: 12 AF XY: 0.479 AC XY: 215279 AN XY: 449638

African (AFR) AF: 0.417 AC: 8543 AN: 20502

American (AMR) AF: 0.641 AC: 13297 AN: 20752

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 6596 AN: 17076

East Asian (EAS) AF: 0.667 AC: 21883 AN: 32828

South Asian (SAS) AF: 0.588 AC: 33162 AN: 56394

European-Finnish (FIN) AF: 0.472 AC: 14262 AN: 30188

Middle Eastern (MID) AF: 0.472 AC: 1369 AN: 2898

European-Non Finnish (NFE) AF: 0.456 AC: 309225 AN: 678414

Other (OTH) AF: 0.476 AC: 19470 AN: 40882

GnomAD4 genome AF: 0.471 AC: 71684 AN: 152074 Hom.: 17269 Cov.: 34 AF XY: 0.478 AC XY: 35528 AN XY: 74322

African (AFR) AF: 0.423 AC: 17572 AN: 41542

American (AMR) AF: 0.592 AC: 9053 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 1356 AN: 3470

East Asian (EAS) AF: 0.642 AC: 3287 AN: 5116

South Asian (SAS) AF: 0.595 AC: 2867 AN: 4822

European-Finnish (FIN) AF: 0.457 AC: 4839 AN: 10588

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.460 AC: 31269 AN: 67932

Other (OTH) AF: 0.484 AC: 1020 AN: 2108

Alfa AF: 0.479 Hom.: 7467

Bravo AF: 0.480

Asia WGS AF: 0.595 AC: 2071 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.2
DANN	Benign	0.79
PhyloP100		0.28
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: rs3745802; hg19: chr19-46271177; COSMIC: COSV52182683; COSMIC: COSV52182683;