rs546842338

Variant names:

• chr8-144517621-C-A
• rs546842338
• ENST00000621189.4:c.-973G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-144517621-C-A
• chr8-144517621-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM2 BP4_Moderate BP6_Very_Strong

The ENST00000621189.4(RECQL4):​c.-973G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000269 in 1,486,496 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 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: RECQL4 ENST00000621189.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.29
• Publications: 0 publications found

Genes affected

RECQL4 (HGNC:9949): (RecQ like helicase 4) The protein encoded by this gene is a DNA helicase that belongs to the RecQ helicase family. DNA helicases unwind double-stranded DNA into single-stranded DNAs and may modulate chromosome segregation. This gene is predominantly expressed in thymus and testis. Mutations in this gene are associated with Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes. [provided by RefSeq, Jan 2010]

RECQL4 Gene-Disease associations (from GenCC):

• Baller-Gerold syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet
• Rothmund-Thomson syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Rothmund-Thomson syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
• osteosarcoma

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• rapadilino syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 8-144517621-C-A is Benign according to our data. Variant chr8-144517621-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 529059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000621189.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	NM_004260.4	MANE Select	c.99G>T	p.Ala33Ala	synonymous	Exon 2 of 21	NP_004251.4
	RECQL4	NM_001413023.1		c.-973G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 19	NP_001399952.1
	RECQL4	NM_001413041.1		c.-1035G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 19	NP_001399970.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000621189.4	TSL:1	c.-973G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 20	ENSP00000483145.1
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.99G>T	p.Ala33Ala	synonymous	Exon 2 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.-973G>T		5_prime_UTR	Exon 1 of 20	ENSP00000483145.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152102 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 86888 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1334286 Hom.: 0 Cov.: 32 AF XY: 0.00000152 AC XY: 1 AN XY: 657956

African (AFR) AF: 0.0000374 AC: 1 AN: 26770

American (AMR) AF: 0.00 AC: 0 AN: 28892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23518

East Asian (EAS) AF: 0.00 AC: 0 AN: 30220

South Asian (SAS) AF: 0.00 AC: 0 AN: 73924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4114

European-Non Finnish (NFE) AF: 9.45e-7 AC: 1 AN: 1058320

Other (OTH) AF: 0.00 AC: 0 AN: 55420

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152210 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74424

African (AFR) AF: 0.0000481 AC: 2 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Baller-Gerold syndrome (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	9.9
DANN	Benign	0.94
PhyloP100		1.3
PromoterAI		-0.091	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.3

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: rs546842338; hg19: chr8-145743005;