chr8-144517765-A-C

Variant names:

• chr8-144517765-A-C
• rs781721739
• NM_004260.4:c.20T>G

Variant summary

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

The NM_001413019.1(RECQL4):​c.20T>G​(p.Val7Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000207 in 1,302,660 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. V7A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000019 (1 hom.)
• Consequence: RECQL4 NM_001413019.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 B:2
• Conservation: PhyloP100: 0.140
• 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]

LRRC14 (HGNC:20419): (leucine rich repeat containing 14) This gene encodes a leucine-rich repeat-containing protein. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.20894387).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	NM_004260.4	MANE Select	c.20T>G	p.Val7Gly	missense	Exon 1 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.20T>G	p.Val7Gly	missense	Exon 1 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.20T>G	p.Val7Gly	missense	Exon 1 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.20T>G	p.Val7Gly	missense	Exon 1 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.-1117T>G		5_prime_UTR	Exon 1 of 20	ENSP00000483145.1
	RECQL4	ENST00000971710.1		c.20T>G	p.Val7Gly	missense	Exon 1 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.0000332 AC: 5 AN: 150618 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000444

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000827 AC: 3 AN: 36282 AF XY: 0.000137

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000164

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000747

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000191 AC: 22 AN: 1152042 Hom.: 1 Cov.: 32 AF XY: 0.0000268 AC XY: 15 AN XY: 559782

African (AFR) AF: 0.00 AC: 0 AN: 22940

American (AMR) AF: 0.000136 AC: 2 AN: 14688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17018

East Asian (EAS) AF: 0.00 AC: 0 AN: 24324

South Asian (SAS) AF: 0.000320 AC: 14 AN: 43800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25402

Middle Eastern (MID) AF: 0.000316 AC: 1 AN: 3166

European-Non Finnish (NFE) AF: 0.00000419 AC: 4 AN: 955104

Other (OTH) AF: 0.0000219 AC: 1 AN: 45600

GnomAD4 genome AF: 0.0000332 AC: 5 AN: 150618 Hom.: 0 Cov.: 34 AF XY: 0.0000272 AC XY: 2 AN XY: 73512

African (AFR) AF: 0.00 AC: 0 AN: 41208

American (AMR) AF: 0.0000661 AC: 1 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000444 AC: 3 AN: 67504

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.000324 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Baller-Gerold syndrome (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Rothmund-Thomson syndrome type 2 (1)
-	1	-	Rothmund-Thomson syndrome;C0265308:Baller-Gerold syndrome;C1849453:Rapadilino syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Benign	0.47
DEOGEN2	Benign	0.17	T
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.22	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.21	T
PhyloP100		0.14
PrimateAI	Pathogenic	0.87	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.97	D
Vest4		0.13
MVP		0.79
GERP RS		3.4
PromoterAI		0.070	Neutral
Varity_R		0.42
gMVP		0.42
Mutation Taster		=83/17	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: rs781721739; hg19: chr8-145743149;