19-18450870-C-T

Variant names:

• chr19-18450870-C-T
• rs757695728
• NM_006532.4:c.1072G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006532.4(ELL):​c.1072G>A​(p.Val358Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000436 in 1,583,154 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (1 hom.)
• Consequence: ELL NM_006532.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0630

Genes affected

ELL (HGNC:23114): (elongation factor for RNA polymerase II) Enables phosphatase binding activity. Involved in positive regulation of transcription, DNA-templated and snRNA transcription. Located in cytosol; nuclear body; and transcriptionally active chromatin. Part of transcription elongation factor complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042903483).
• BP6: Variant 19-18450870-C-T is Benign according to our data. Variant chr19-18450870-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2237116.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELL	NM_006532.4	c.1072G>A	p.Val358Met	missense_variant	Exon 8 of 12	ENST00000262809.9	NP_006523.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELL	ENST00000262809.9	c.1072G>A	p.Val358Met	missense_variant	Exon 8 of 12	1	NM_006532.4	ENSP00000262809.3
ELL	ENST00000596124.3	c.673G>A	p.Val225Met	missense_variant	Exon 8 of 12	1		ENSP00000475648.2
ELL	ENST00000594635.6	n.*907G>A		non_coding_transcript_exon_variant	Exon 9 of 13	1		ENSP00000475681.2
ELL	ENST00000594635.6	n.*907G>A		3_prime_UTR_variant	Exon 9 of 13	1		ENSP00000475681.2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000758 AC: 17 AN: 224348 AF XY: 0.0000896

Gnomad AFR exome AF: 0.000272

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000488

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 51 AN: 1430974 Hom.: 1 Cov.: 32 AF XY: 0.0000508 AC XY: 36 AN XY: 708722

Gnomad4 AFR exome AF: 0.000154 AC: 5 AN: 32396

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 39722

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 24566

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39190

Gnomad4 SAS exome AF: 0.000335 AC: 28 AN: 83632

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 51508

Gnomad4 NFE exome AF: 0.0000137 AC: 15 AN: 1095506

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 58840

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74338

Gnomad4 AFR AF: 0.000266 AC: 0.000265547 AN: 0.000265547

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000414 AC: 0.000413565 AN: 0.000413565

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000735 AC: 0.0000734819 AN: 0.0000734819

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000744 AC: 9

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 14, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.6
DANN	Benign	0.82
DEOGEN2	Benign	0.057	T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.35	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.043	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.41	N;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.11	N;.
REVEL	Benign	0.019
Sift	Benign	0.24	T;.
Sift4G	Benign	0.16	T;T
Polyphen		0.012	B;.
Vest4		0.13
MVP		0.32
MPC		0.024
ClinPred		0.018	T
GERP RS		-7.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.030
gMVP		0.15
Mutation Taster		=94/6	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

Publications

LitVar

Other links and lift over

dbSNP: rs757695728; hg19: chr19-18561680;