8-144516029-C-T

Variant names:

• chr8-144516029-C-T
• rs144637135
• NM_004260.4:c.1090G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001413041.1(RECQL4):​c.-44G>A 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 0.000799 in 1,611,570 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (2 hom.)
• Consequence: RECQL4 NM_001413041.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 1.06
• Publications: 5 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, SUPPORTIVE Submitted by: Orphanet, G2P
• Rothmund-Thomson syndrome

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

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

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054152906).
• BP6: Variant 8-144516029-C-T is Benign according to our data. Variant chr8-144516029-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00402 (612/152338) while in subpopulation AFR AF = 0.0135 (562/41556). AF 95% confidence interval is 0.0126. There are 3 homozygotes in GnomAd4. There are 277 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001413041.1. 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
	RECQL4	NM_004260.4	MANE Select	c.1090G>A	p.Val364Met	missense	Exon 5 of 21	NP_004251.4	O94761
	RECQL4	NM_001413041.1		c.-44G>A		5_prime_UTR_premature_start_codon_gain	Exon 4 of 19	NP_001399970.1
	RECQL4	NM_001413027.1		c.-44G>A		5_prime_UTR_premature_start_codon_gain	Exon 5 of 21	NP_001399956.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.1090G>A	p.Val364Met	missense	Exon 5 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.19G>A	p.Val7Met	missense	Exon 4 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.1090G>A	p.Val364Met	missense	Exon 5 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.00403 AC: 613 AN: 152220 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

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: 0.000103

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00116 AC: 287 AN: 247560 AF XY: 0.000823

Gnomad AFR exome AF: 0.0157

Gnomad AMR exome AF: 0.000638

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000152

Gnomad OTH exome AF: 0.000999

GnomAD4 exome AF: 0.000463 AC: 676 AN: 1459232 Hom.: 2 Cov.: 66 AF XY: 0.000423 AC XY: 307 AN XY: 725650

African (AFR) AF: 0.0139 AC: 466 AN: 33462

American (AMR) AF: 0.000783 AC: 35 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26102

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39658

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52042

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5764

European-Non Finnish (NFE) AF: 0.0000882 AC: 98 AN: 1110958

Other (OTH) AF: 0.000945 AC: 57 AN: 60312

GnomAD4 genome AF: 0.00402 AC: 612 AN: 152338 Hom.: 3 Cov.: 33 AF XY: 0.00372 AC XY: 277 AN XY: 74492

African (AFR) AF: 0.0135 AC: 562 AN: 41556

American (AMR) AF: 0.00229 AC: 35 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68040

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00169 Hom.: 2

Bravo AF: 0.00467

ESP6500AA AF: 0.0123 AC: 51

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00151 AC: 182

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (3)
-	-	1	Baller-Gerold syndrome (1)
-	-	1	Rapadilino syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.78
DEOGEN2	Benign	0.033	T
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0054	T
PhyloP100		1.1
PrimateAI	Benign	0.40	T
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.26
MVP		0.32
GERP RS		2.7
PromoterAI		0.0050	Neutral
Varity_R		0.018
gMVP		0.35
Mutation Taster		=96/4	polymorphism

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: rs144637135; hg19: chr8-145741413; COSMIC: COSV104618532;