rs781636798

Variant names:

• chr8-144513017-G-A
• rs781636798
• NM_004260.4:c.2585C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-144513017-G-A
• chr8-144513017-G-C
• chr8-144513017-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001413019.1(RECQL4):​c.2585C>T​(p.Ser862Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000528 in 1,571,684 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S862T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000058 (1 hom.)
• Consequence: RECQL4 NM_001413019.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 B:2
• Conservation: PhyloP100: -1.81
• 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, 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

ENSG00000265393 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07679117).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001413019.1. 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.2585C>T	p.Ser862Leu	missense	Exon 15 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.2585C>T	p.Ser862Leu	missense	Exon 15 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.2585C>T	p.Ser862Leu	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.2585C>T	p.Ser862Leu	missense	Exon 15 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.1514C>T	p.Ser505Leu	missense	Exon 14 of 20	ENSP00000483145.1
	RECQL4	ENST00000971710.1		c.2492C>T	p.Ser831Leu	missense	Exon 15 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

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: 0.0000658 AC: 12 AN: 182372 AF XY: 0.0000811

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000112

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000520

Gnomad OTH exome AF: 0.000612

GnomAD4 exome AF: 0.0000578 AC: 82 AN: 1419450 Hom.: 1 Cov.: 66 AF XY: 0.0000712 AC XY: 50 AN XY: 702364

African (AFR) AF: 0.0000308 AC: 1 AN: 32480

American (AMR) AF: 0.0000787 AC: 3 AN: 38118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25430

East Asian (EAS) AF: 0.00 AC: 0 AN: 37246

South Asian (SAS) AF: 0.000246 AC: 20 AN: 81282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49082

Middle Eastern (MID) AF: 0.000524 AC: 3 AN: 5720

European-Non Finnish (NFE) AF: 0.0000412 AC: 45 AN: 1091272

Other (OTH) AF: 0.000170 AC: 10 AN: 58820

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152234 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74374

African (AFR) AF: 0.0000241 AC: 1 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000338 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	1	-	Baller-Gerold syndrome (1)
-	1	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.1
DANN	Benign	0.59
DEOGEN2	Benign	0.0040	T
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.077	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.8
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.30	T
Polyphen		0.0020	B
Vest4		0.14
MVP		0.71
GERP RS		-0.80
PromoterAI		0.0014	Neutral
Varity_R		0.044
gMVP		0.35
Mutation Taster		=85/15	polymorphism

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: rs781636798; hg19: chr8-145738400;