14-70458656-C-G

Position:

• chr14-70458656-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003813.4(ADAM21):​c.1157C>G​(p.Thr386Ser) 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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: ADAM21 NM_003813.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.951

Genes affected

ADAM21 (HGNC:200): (ADAM metallopeptidase domain 21) This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The expression of this gene expression is testis-specific. [provided by RefSeq, May 2011]

(HGNC:):

ADAM20P1 (HGNC:20102): (ADAM metallopeptidase domain 20 pseudogene 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19518778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM21	NM_003813.4	c.1157C>G	p.Thr386Ser	missense_variant	2/2	ENST00000603540.2	NP_003804.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM21	ENST00000603540.2	c.1157C>G	p.Thr386Ser	missense_variant	2/2	3	NM_003813.4	ENSP00000474385	P1
	ENST00000556646.1	n.184-5147G>C		intron_variant, non_coding_transcript_variant		4
ADAM20P1	ENST00000649019.1	n.506+1794G>C		intron_variant, non_coding_transcript_variant
ADAM21	ENST00000679631.1	c.1157C>G	p.Thr386Ser	missense_variant	2/2			ENSP00000506213	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2023

The c.1157C>G (p.T386S) alteration is located in exon 2 (coding exon 1) of the ADAM21 gene. This alteration results from a C to G substitution at nucleotide position 1157, causing the threonine (T) at amino acid position 386 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
Sift4G	Benign	0.48	T
Polyphen		0.0090	B
Vest4		0.48
MutPred		0.56		Gain of ubiquitination at K385 (P = 0.1062);
MVP		0.58
MPC		0.45
ClinPred		0.12	T
GERP RS		3.1
Varity_R		0.17
gMVP		0.51

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: chr14-70925373;