rs778939539

Variant names:

• chr8-144512889-G-A
• rs778939539
• NM_004260.4:c.2713C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-144512889-G-A
• chr8-144512889-G-C
• chr8-144512889-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004260.4(RECQL4):​c.2713C>T​(p.Pro905Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,442,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/14 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. P905A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.21
• Publications: 2 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29560876).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	NM_004260.4	MANE Select	c.2713C>T	p.Pro905Ser	missense	Exon 15 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.2713C>T	p.Pro905Ser	missense	Exon 15 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.2713C>T	p.Pro905Ser	missense	Exon 15 of 21	NP_001399965.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.2713C>T	p.Pro905Ser	missense	Exon 15 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.1642C>T	p.Pro548Ser	missense	Exon 14 of 20	ENSP00000483145.1
	RECQL4	ENST00000534626.6	TSL:5	c.883C>T	p.Pro295Ser	missense	Exon 6 of 8	ENSP00000477457.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000138 AC: 3 AN: 216612 AF XY: 0.0000170

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000189

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1442054 Hom.: 0 Cov.: 67 AF XY: 0.00000419 AC XY: 3 AN XY: 715650

African (AFR) AF: 0.00 AC: 0 AN: 33138

American (AMR) AF: 0.00 AC: 0 AN: 42034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25614

East Asian (EAS) AF: 0.0000773 AC: 3 AN: 38824

South Asian (SAS) AF: 0.00 AC: 0 AN: 83646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102640

Other (OTH) AF: 0.00 AC: 0 AN: 59644

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000167 AC: 2

ClinVar

ClinVar submissions as Germline

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	0.20
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	18
DANN	Benign	0.83
DEOGEN2	Benign	0.064	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.30	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.2
PrimateAI	Benign	0.43	T
Sift4G	Benign	0.51	T
Polyphen		0.26	B
Vest4		0.41
MVP		0.73
GERP RS		3.1
PromoterAI		-0.0023	Neutral
Varity_R		0.10
gMVP		0.47
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs778939539; hg19: chr8-145738272;