8-144512966-G-T

Variant names:

• chr8-144512966-G-T
• rs137975310
• NM_004260.4:c.2636C>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_004260.4(RECQL4):​c.2636C>A​(p.Pro879His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00995 in 1,571,768 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 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. P879A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0089 (7 hom., cov: 34)
  • Exomes 𝑓: 0.010 (90 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.280
• Publications: 10 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

ENSG00000265393 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.004400462).
• BP6: Variant 8-144512966-G-T is Benign according to our data. Variant chr8-144512966-G-T is described in ClinVar as Benign. ClinVar VariationId is 94890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0089 (1355/152308) while in subpopulation AMR AF = 0.0157 (240/15308). AF 95% confidence interval is 0.0141. There are 7 homozygotes in GnomAd4. There are 633 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.2636C>A	p.Pro879His	missense	Exon 15 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.2636C>A	p.Pro879His	missense	Exon 15 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.2636C>A	p.Pro879His	missense	Exon 15 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.2636C>A	p.Pro879His	missense	Exon 15 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.1565C>A	p.Pro522His	missense	Exon 14 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.2543C>A	p.Pro848His	missense	Exon 15 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.00890 AC: 1355 AN: 152190 Hom.: 7 Cov.: 34

Gnomad AFR AF: 0.00511

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00763 AC: 1399 AN: 183400 AF XY: 0.00768

Gnomad AFR exome AF: 0.00429

Gnomad AMR exome AF: 0.0107

Gnomad ASJ exome AF: 0.0131

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000742

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0101 AC: 14291 AN: 1419460 Hom.: 90 Cov.: 66 AF XY: 0.00994 AC XY: 6980 AN XY: 702330

African (AFR) AF: 0.00480 AC: 156 AN: 32484

American (AMR) AF: 0.0115 AC: 441 AN: 38372

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 331 AN: 25454

East Asian (EAS) AF: 0.00 AC: 0 AN: 37310

South Asian (SAS) AF: 0.00311 AC: 253 AN: 81294

European-Finnish (FIN) AF: 0.00118 AC: 58 AN: 49098

Middle Eastern (MID) AF: 0.0284 AC: 162 AN: 5714

European-Non Finnish (NFE) AF: 0.0112 AC: 12220 AN: 1090910

Other (OTH) AF: 0.0114 AC: 670 AN: 58824

GnomAD4 genome AF: 0.00890 AC: 1355 AN: 152308 Hom.: 7 Cov.: 34 AF XY: 0.00850 AC XY: 633 AN XY: 74488

African (AFR) AF: 0.00508 AC: 211 AN: 41570

American (AMR) AF: 0.0157 AC: 240 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4822

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10620

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0113 AC: 767 AN: 68008

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.00724 Hom.: 3

Bravo AF: 0.00965

ESP6500AA AF: 0.00403 AC: 16

ESP6500EA AF: 0.00759 AC: 63

ExAC AF: 0.00559 AC: 660

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: 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)
-	-	1	Rothmund-Thomson syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.50
DANN	Benign	0.59
DEOGEN2	Benign	0.027	T
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0044	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.28
PrimateAI	Benign	0.32	T
Sift4G	Benign	0.13	T
Polyphen		0.39	B
Vest4		0.23
MVP		0.74
GERP RS		0.48
PromoterAI		-0.0062	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.034
gMVP		0.33
Mutation Taster		=97/3	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: rs137975310; hg19: chr8-145738349; COSMIC: COSV56742751; COSMIC: COSV56742751;