chr5-163469773-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001142556.2(HMMR):ā€‹c.406A>Gā€‹(p.Thr136Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,612,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000033 ( 0 hom., cov: 32)
Exomes š‘“: 0.000038 ( 0 hom. )

Consequence

HMMR
NM_001142556.2 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.87
Variant links:
Genes affected
HMMR (HGNC:5012): (hyaluronan mediated motility receptor) The protein encoded by this gene is involved in cell motility. It is expressed in breast tissue and together with other proteins, it forms a complex with BRCA1 and BRCA2, thus is potentially associated with higher risk of breast cancer. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Dec 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.04510957).
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HMMRNM_001142556.2 linkuse as main transcriptc.406A>G p.Thr136Ala missense_variant 5/18 ENST00000393915.9 NP_001136028.1 O75330-3
HMMRNM_012484.3 linkuse as main transcriptc.403A>G p.Thr135Ala missense_variant 5/18 NP_036616.2 O75330-1
HMMRNM_012485.3 linkuse as main transcriptc.358A>G p.Thr120Ala missense_variant 4/17 NP_036617.2 O75330-2
HMMRNM_001142557.2 linkuse as main transcriptc.145A>G p.Thr49Ala missense_variant 2/15 NP_001136029.1 O75330-4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HMMRENST00000393915.9 linkuse as main transcriptc.406A>G p.Thr136Ala missense_variant 5/181 NM_001142556.2 ENSP00000377492.4 O75330-3
HMMRENST00000520345.5 linkuse as main transcriptc.61A>G p.Thr21Ala missense_variant 4/62 ENSP00000428481.1 E5RI30

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152234
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251218
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135816
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000377
AC:
55
AN:
1460096
Hom.:
0
Cov.:
30
AF XY:
0.0000399
AC XY:
29
AN XY:
726490
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000104
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000369
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152352
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74504
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000480
Hom.:
0
Bravo
AF:
0.0000151
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

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 submitterclinical testingAmbry GeneticsOct 27, 2021The c.406A>G (p.T136A) alteration is located in exon 5 (coding exon 5) of the HMMR gene. This alteration results from a A to G substitution at nucleotide position 406, causing the threonine (T) at amino acid position 136 to be replaced by an alanine (A). 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
0.068
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
12
DANN
Benign
0.88
DEOGEN2
Benign
0.10
T;.;.;.;.;T
Eigen
Benign
-0.97
Eigen_PC
Benign
-0.74
FATHMM_MKL
Benign
0.72
D
LIST_S2
Benign
0.51
T;T;T;T;T;T
M_CAP
Benign
0.025
T
MetaRNN
Benign
0.045
T;T;T;T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
0.81
.;.;.;.;.;L
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-0.29
N;N;N;N;N;N
REVEL
Benign
0.060
Sift
Benign
0.054
T;T;T;T;T;T
Sift4G
Benign
0.24
T;T;T;T;T;T
Polyphen
0.0
.;.;B;B;B;B
Vest4
0.037, 0.028, 0.046
MVP
0.64
MPC
0.059
ClinPred
0.022
T
GERP RS
2.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.026
gMVP
0.048

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201404287; hg19: chr5-162896779; API