rs2721190

Variant names:

• chr8-144517130-A-G
• rs2721190
• NM_004260.4:c.274T>C

Your query was ambiguous. Multiple possible variants found:

• chr8-144517130-A-G
• chr8-144517130-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004260.4(RECQL4):​c.274T>C​(p.Ser92Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.989 in 1,612,104 control chromosomes in the GnomAD database, including 789,429 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/12 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. S92F) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.98 (73726 hom., cov: 38)
  • Exomes 𝑓: 0.99 (715703 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.157
• Publications: 44 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=8.1035216E-7).
• BP6: Variant 8-144517130-A-G is Benign according to our data. Variant chr8-144517130-A-G is described in ClinVar as Benign. ClinVar VariationId is 135161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

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.274T>C	p.Ser92Pro	missense	Exon 4 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.274T>C	p.Ser92Pro	missense	Exon 4 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.274T>C	p.Ser92Pro	missense	Exon 4 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.274T>C	p.Ser92Pro	missense	Exon 4 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.-798T>C		5_prime_UTR	Exon 3 of 20	ENSP00000483145.1
	RECQL4	ENST00000524998.1	TSL:3	c.145T>C	p.Ser49Pro	missense	Exon 2 of 4	ENSP00000476579.1

Frequencies

GnomAD3 genomes AF: 0.983 AC: 149666 AN: 152260 Hom.: 73665 Cov.: 38

Gnomad AFR AF: 0.983

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.949

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 0.804

Gnomad SAS AF: 0.997

Gnomad FIN AF: 0.998

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.986

GnomAD2 exomes AF: 0.970 AC: 237760 AN: 245198 AF XY: 0.975

Gnomad AFR exome AF: 0.982

Gnomad AMR exome AF: 0.902

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 0.803

Gnomad FIN exome AF: 0.997

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.981

GnomAD4 exome AF: 0.989 AC: 1444084 AN: 1459726 Hom.: 715703 Cov.: 73 AF XY: 0.990 AC XY: 718854 AN XY: 726162

African (AFR) AF: 0.984 AC: 32956 AN: 33476

American (AMR) AF: 0.908 AC: 40490 AN: 44610

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26099 AN: 26100

East Asian (EAS) AF: 0.758 AC: 30071 AN: 39678

South Asian (SAS) AF: 0.999 AC: 86080 AN: 86208

European-Finnish (FIN) AF: 0.996 AC: 51704 AN: 51894

Middle Eastern (MID) AF: 0.996 AC: 5735 AN: 5758

European-Non Finnish (NFE) AF: 1.00 AC: 1111310 AN: 1111686

Other (OTH) AF: 0.989 AC: 59639 AN: 60316

GnomAD4 genome AF: 0.983 AC: 149786 AN: 152378 Hom.: 73726 Cov.: 38 AF XY: 0.982 AC XY: 73148 AN XY: 74516

African (AFR) AF: 0.983 AC: 40899 AN: 41596

American (AMR) AF: 0.949 AC: 14536 AN: 15312

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 0.804 AC: 4158 AN: 5174

South Asian (SAS) AF: 0.997 AC: 4819 AN: 4834

European-Finnish (FIN) AF: 0.998 AC: 10608 AN: 10632

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68002 AN: 68036

Other (OTH) AF: 0.986 AC: 2086 AN: 2116

Alfa AF: 0.991 Hom.: 111420

Bravo AF: 0.978

TwinsUK AF: 1.00 AC: 3707

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.986 AC: 3869

ESP6500EA AF: 0.999 AC: 8276

ExAC AF: 0.973 AC: 116620

Asia WGS AF: 0.945 AC: 3285 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Baller-Gerold syndrome Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1 Other:1

Aug 02, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Rapadilino syndrome Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Rothmund-Thomson syndrome type 2 Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.5
DANN	Benign	0.45
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	8.1e-7	T
PhyloP100		0.16
PrimateAI	Benign	0.34	T
Sift4G	Benign	0.39	T
Vest4		0.041
GERP RS		2.0
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.070
gMVP		0.14
Mutation Taster		=95/5	polymorphism (auto)

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: rs2721190; hg19: chr8-145742514; COSMIC: COSV52881402; COSMIC: COSV52881402;