Variant 9-136854211-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_206920.3(MAMDC4):c.671C>T(p.Thr224Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MAMDC4
NM_206920.3 missense, splice_region

Scores

Splicing: ADA: 0.00008704

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0180

Variant links:

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]

MAMDC4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.052904367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAMDC4	NM_206920.3 linkuse as main transcript	c.671C>T	p.Thr224Ile	missense_variant, splice_region_variant	7/27	ENST00000317446.7	NP_996803.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAMDC4	ENST00000317446.7 linkuse as main transcript	c.671C>T	p.Thr224Ile	missense_variant, splice_region_variant	7/27	1	NM_206920.3	ENSP00000319388		Q6UXC1-2
MAMDC4	ENST00000485732.5 linkuse as main transcript	n.1107C>T		splice_region_variant, non_coding_transcript_exon_variant	7/25	1
MAMDC4	ENST00000445819.5 linkuse as main transcript	c.671C>T	p.Thr224Ile	missense_variant, splice_region_variant	7/29	5		ENSP00000411339	P1	Q6UXC1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459482

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726020

show subpopulations

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:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2023

The c.671C>T (p.T224I) alteration is located in exon 7 (coding exon 7) of the MAMDC4 gene. This alteration results from a C to T substitution at nucleotide position 671, causing the threonine (T) at amino acid position 224 to be replaced by an isoleucine (I). 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

-0.28

BayesDel_noAF

Benign

-0.63

CADD

Benign

4.3

DANN

Benign

0.90

DEOGEN2

Benign

0.0058

.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.53

T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.053

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.2

L;L

MutationTaster

Benign

0.93

N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.96

N;N

REVEL

Benign

0.0050

Sift

Benign

0.23

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.0020

B;.

Vest4

0.16

MutPred

0.42

Loss of glycosylation at T224 (P = 0.0346);Loss of glycosylation at T224 (P = 0.0346);

MVP

0.085

MPC

0.024

ClinPred

0.049

GERP RS

-1.9

Varity_R

0.037

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000087

dbscSNV1_RF

Benign

0.056

SpliceAI score (max)

0.060

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over