chr8-144516364-G-A

Variant names:

• chr8-144516364-G-A
• rs199773279
• NM_004260.4:c.755C>T

Variant summary

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

The NM_004260.4(RECQL4):​c.755C>T​(p.Pro252Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,610,090 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P252S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (11 hom., cov: 34)
  • Exomes 𝑓: 0.0025 (117 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.618
• Publications: 7 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=0.005003482).
• BP6: Variant 8-144516364-G-A is Benign according to our data. Variant chr8-144516364-G-A is described in ClinVar as Benign. ClinVar VariationId is 135165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00143 (218/152338) while in subpopulation SAS AF = 0.0435 (210/4826). AF 95% confidence interval is 0.0387. There are 11 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004260.4. 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.755C>T	p.Pro252Leu	missense	Exon 5 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.755C>T	p.Pro252Leu	missense	Exon 5 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.755C>T	p.Pro252Leu	missense	Exon 5 of 21	NP_001399965.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.755C>T	p.Pro252Leu	missense	Exon 5 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.-317C>T		5_prime_UTR	Exon 4 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.755C>T	p.Pro252Leu	missense	Exon 5 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152220 Hom.: 11 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0437

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00532 AC: 1298 AN: 243952 AF XY: 0.00689

Gnomad AFR exome AF: 0.0000667

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000721

Gnomad OTH exome AF: 0.00319

GnomAD4 exome AF: 0.00254 AC: 3708 AN: 1457752 Hom.: 117 Cov.: 64 AF XY: 0.00368 AC XY: 2668 AN XY: 725140

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39694

South Asian (SAS) AF: 0.0400 AC: 3447 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49864

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1111678

Other (OTH) AF: 0.00318 AC: 192 AN: 60336

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152338 Hom.: 11 Cov.: 34 AF XY: 0.00216 AC XY: 161 AN XY: 74502

African (AFR) AF: 0.0000481 AC: 2 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0435 AC: 210 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000641 Hom.: 0

Bravo AF: 0.000295

ExAC AF: 0.00613 AC: 739

Asia WGS AF: 0.0180 AC: 62 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	8.0
DANN	Benign	0.73
DEOGEN2	Benign	0.073	T
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0050	T
PhyloP100		0.62
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.28	T
Polyphen		0.011	B
Vest4		0.19
MVP		0.70
GERP RS		-0.014
PromoterAI		-0.0085	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
Varity_R		0.028
gMVP		0.20
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs199773279; hg19: chr8-145741748;