8-144511912-C-T

Variant names:

• chr8-144511912-C-T
• rs201369291
• NM_004260.4:c.3392G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_004260.4(RECQL4):​c.3392G>A​(p.Arg1131Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000471 in 1,610,652 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1131I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 35)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense, splice_region
• Scores: Splicing: ADA: 0.00002453
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.543
• Publications: 1 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006081164).
• BP6: Variant 8-144511912-C-T is Benign according to our data. Variant chr8-144511912-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 239761.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00245 (373/152398) while in subpopulation AFR AF = 0.00863 (359/41594). AF 95% confidence interval is 0.0079. There are 1 homozygotes in GnomAd4. There are 181 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

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.3392G>A	p.Arg1131Lys	missense splice_region	Exon 19 of 21	NP_004251.4	O94761
	RECQL4	NM_001413036.1		c.3392G>A	p.Arg1131Lys	missense	Exon 19 of 21	NP_001399965.1
	RECQL4	NM_001413019.1		c.3467G>A	p.Arg1156Lys	missense splice_region	Exon 18 of 20	NP_001399948.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.3392G>A	p.Arg1131Lys	missense splice_region	Exon 19 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.2321G>A	p.Arg774Lys	missense splice_region	Exon 18 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000531875.2	TSL:5	c.638G>A	p.Arg213Lys	missense	Exon 4 of 6	ENSP00000477910.1	A0A087WTJ0

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 372 AN: 152280 Hom.: 1 Cov.: 35

Gnomad AFR AF: 0.00863

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

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: 0.00191

GnomAD2 exomes AF: 0.000619 AC: 152 AN: 245556 AF XY: 0.000485

Gnomad AFR exome AF: 0.00890

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.000334

GnomAD4 exome AF: 0.000264 AC: 385 AN: 1458254 Hom.: 0 Cov.: 57 AF XY: 0.000216 AC XY: 157 AN XY: 725462

African (AFR) AF: 0.0102 AC: 340 AN: 33474

American (AMR) AF: 0.000358 AC: 16 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111692

Other (OTH) AF: 0.000414 AC: 25 AN: 60330

GnomAD4 genome AF: 0.00245 AC: 373 AN: 152398 Hom.: 1 Cov.: 35 AF XY: 0.00243 AC XY: 181 AN XY: 74530

African (AFR) AF: 0.00863 AC: 359 AN: 41594

American (AMR) AF: 0.000653 AC: 10 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000704 Hom.: 0

Bravo AF: 0.00267

ESP6500AA AF: 0.00788 AC: 34

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.000697 AC: 84

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Baller-Gerold syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	RECQL4-related disorder (1)
-	1	-	Rothmund-Thomson syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.049
DANN	Benign	0.65
DEOGEN2	Benign	0.0021	T
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.0061	T
MutationAssessor	Benign	0.040	N
PhyloP100		-0.54
PrimateAI	Benign	0.24	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.70
GERP RS		-2.3
Varity_R		0.024
gMVP		0.17
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0020
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: rs201369291; hg19: chr8-145737295;