8-38105657-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_004674.5(ASH2L):c.107C>T(p.Ala36Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ASH2L NM_004674.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.167

Genes affected

ASH2L (HGNC:744): (ASH2 like, histone lysine methyltransferase complex subunit) Enables beta-catenin binding activity and transcription cis-regulatory region binding activity. Contributes to histone methyltransferase activity (H3-K4 specific). Involved in histone H3-K4 methylation; positive regulation of cell population proliferation; and response to estrogen. Acts upstream of or within cellular response to DNA damage stimulus. Located in nucleus. Part of MLL3/4 complex and Set1C/COMPASS complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08006477).
• BP6: Variant 8-38105657-C-T is Benign according to our data. Variant chr8-38105657-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2321422.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASH2L	NM_004674.5	c.107C>T	p.Ala36Val	missense_variant	1/16	ENST00000343823.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASH2L	ENST00000343823.11	c.107C>T	p.Ala36Val	missense_variant	1/16	1	NM_004674.5
ASH2L	ENST00000517719.5	c.107C>T	p.Ala36Val	missense_variant	1/5	3
ASH2L	ENST00000545394.2	c.-165C>T		5_prime_UTR_variant	1/15	2
ASH2L	ENST00000517496.5	c.107C>T	p.Ala36Val	missense_variant, NMD_transcript_variant	1/15	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1440368 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 715942

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2022

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	0.071
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.089	T;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.20	N;N
REVEL	Benign	0.12
Sift	Benign	0.22	T;T
Sift4G	Uncertain	0.042	D;D
Polyphen		0.0	B;.
Vest4		0.037
MutPred		0.21		Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);
MVP		0.54
MPC		0.011
ClinPred		0.13	T
GERP RS		-0.61
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
Varity_R		0.038
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-37963175;