rs768797926

Variant names:

• chr8-144512888-G-A
• rs768797926
• NM_004260.4:c.2714C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004260.4(RECQL4):​c.2714C>T​(p.Pro905Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,441,992 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P905A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.32
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2714C>T	p.Pro905Leu	missense	Exon 15 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.2714C>T	p.Pro905Leu	missense	Exon 15 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.2714C>T	p.Pro905Leu	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.2714C>T	p.Pro905Leu	missense	Exon 15 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.1643C>T	p.Pro548Leu	missense	Exon 14 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.2621C>T	p.Pro874Leu	missense	Exon 15 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000924 AC: 2 AN: 216428 AF XY: 0.00000850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000323

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000104

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1441992 Hom.: 0 Cov.: 66 AF XY: 0.00000140 AC XY: 1 AN XY: 715634

African (AFR) AF: 0.00 AC: 0 AN: 33116

American (AMR) AF: 0.0000238 AC: 1 AN: 42046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25608

East Asian (EAS) AF: 0.00 AC: 0 AN: 38828

South Asian (SAS) AF: 0.00 AC: 0 AN: 83660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102556

Other (OTH) AF: 0.00 AC: 0 AN: 59648

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000835 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Baller-Gerold syndrome (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	22
DANN	Benign	0.85
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.55	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		2.3
PrimateAI	Benign	0.48	T
Sift4G	Uncertain	0.047	D
Polyphen		0.97	D
Vest4		0.46
MVP		0.76
GERP RS		4.3
PromoterAI		-0.00080	Neutral
Varity_R		0.17
gMVP		0.50
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs768797926; hg19: chr8-145738271;