9-136853324-C-T

Position:

• chr9-136853324-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_206920.3(MAMDC4):​c.194C>T​(p.Ala65Val) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MAMDC4 NM_206920.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

Genes affected

MAMDC4 (HGNC:24083): (MAM domain containing 4) Predicted to be involved in protein transport. Predicted to be located in membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3621583).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAMDC4	NM_206920.3	c.194C>T	p.Ala65Val	missense_variant	3/27	ENST00000317446.7	NP_996803.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAMDC4	ENST00000317446.7	c.194C>T	p.Ala65Val	missense_variant	3/27	1	NM_206920.3	ENSP00000319388
MAMDC4	ENST00000485732.5	n.438C>T		non_coding_transcript_exon_variant	5/25	1
MAMDC4	ENST00000445819.5	c.194C>T	p.Ala65Val	missense_variant	3/29	5		ENSP00000411339	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Mar 27, 2023

The c.194C>T (p.A65V) alteration is located in exon 3 (coding exon 3) of the MAMDC4 gene. This alteration results from a C to T substitution at nucleotide position 194, causing the alanine (A) at amino acid position 65 to be replaced by a valine (V). 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	0.081
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0071	.;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.058
Sift	Benign	0.14	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.0	B;.
Vest4		0.13
MutPred		0.55		Loss of disorder (P = 0.1019);Loss of disorder (P = 0.1019);
MVP		0.22
MPC		0.023
ClinPred		0.12	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.053
gMVP		0.15

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: chr9-139747776;